Tetra-, penta-, hexa-  and heptapeptides having antiangiogenic activity

ABSTRACT

Compounds of formula (SEQ ID NO:2) and (SEQ ID NO:3), which are useful for treating conditions that arise from or are exacerbated by angiogenesis, are described. Also disclosed are pharmaceutical compositions comprising these compounds, methods of treatment using these compounds, and methods of inhibiting angiogenesis.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationSer. No. 60/335,019, filed on Oct. 31, 2001, and U.S. Provisional PatentApplication Ser. No. 60/335,412, filed on Oct. 31, 2001, which are bothhereby incorporated by reference.

TECHNICAL FIELD

The present invention relates to methods of inhibiting angiogenesis,methods of treating cancer, and compounds having activity useful fortreating conditions which arise from or are exacerbated by angiogenesis.Also disclosed are pharmaceutical compositions comprising the compoundsand methods of treatment using the compounds.

BACKGROUND OF THE INVENTION

Angiogenesis is the fundamental process by which new blood vessels areformed and is essential to a variety of normal body activities (such asreproduction, development and wound repair). Although the process is notcompletely understood, it is believed to involve a complex interplay ofmolecules which both stimulate and inhibit the growth of endothelialcells, the primary cells of the capillary blood vessels. Under normalconditions these molecules appear to maintain the microvasculature in aquiescent state (i.e., one of no capillary growth) for prolonged periodsthat may last for weeks, or in some cases, decades. However, whennecessary, such as during wound repair, these same cells can undergorapid proliferation and turnover within as little as five days.

Although angiogenesis is a highly regulated process under normalconditions, many diseases (characterized as “angiogenic diseases”) aredriven by persistent unregulated angiogenesis. Otherwise stated,unregulated angiogenesis may either cause a particular disease directlyor exacerbate an existing pathological condition. For example, thegrowth and metastasis of solid tumors have been shown to beangiogenesis-dependent. Based on these findings, there is a continuingneed for compounds which demonstrate antiangiogenic activity due totheir potential use in the treatment of various diseases such as cancer.

Peptides having angiogenesis inhibiting properties have been describedin commonly-owned WO01/38397, WO01/38347, WO99/61476, and U.S. patentapplication Ser. No. 09/915,956. However, it would be desirable toprepare antiangiogenic compounds having improved profiles of activityand smaller size.

SUMMARY OF THE INVENTION

The present invention relates to a novel class of compounds havingangiogenesis-inhibiting properties. The invention provides tetra-,penta-, hexa-, and heptapeptides with enhanced properties ofangiogenesis inhibition. In its principle embodiment, the presentinvention provides a compound of formula (I)Xaa₁-Xaa₂-Xaa₃-Xaa₄-Xaa₅-Xaa₆-Xaa₇-Xaa₈  (I),(SEQ ID NO:1)or a therapeutically acceptable salt thereof, wherein

Xaa₁ is selected from the group consisting of hydrogen andR—(CH₂)_(n)—C(O)—, wherein n is an integer from 0 to 8 and R is selectedfrom the group consisting of alkoxy, alkyl, amino, aryl, carboxyl,cycloalkenyl, cycloalkyl, and heterocycle;

Xaa₂ is absent or selected from the group consisting of β-alanyl,D-alanyl, D-alloisoleucyl, D-allylglycyl, D-4-chlorophenylalanyl,D-citrullyl, D-3-cyanophenylalanyl, D-homophenylalanyl, D-homoseryl,isoleucyl, D-isoleucyl, D-leucyl, N-methyl-D-leucyl, D-norleucyl,D-norvalyl, D-penicillaminyl, D-phenylalanyl, D-prolyl, D-seryl,D-thienylalanyl, and D-threonyl;

Xaa₃ is selected from the group consisting of D-alanyl, D-alloisoleucyl,allothreonyl, allylglycyl, asparaginyl, aspartyl, glutaminyl,D-glutaminyl, N-methylglutaminyl, glutamyl, N-methylglutamyl, glycyl,histidyl, homoseryl, D-homoseryl, isoleucyl, D-isoleucyl,lysyl(N-epsilon-acetyl), methionyl, D-methionyl, norleucyl, D-norleucyl,norvalyl, D-norvalyl, D-prolyl, sarcosyl, seryl, D-seryl, N-methylseryl,threonyl, D-threonyl, tryptyl, tyrosyl, and tyrosyl(O-methyl);

Xaa₄ is selected from the group consisting of N-methylalanyl,allothreonyl, arginyl, asparaginyl, D-asparaginyl, citrullyl,glutaminyl, D-glutaminyl, glutamyl, glycyl, homoseryl, leucyl, D-leucyl,lysyl(N-epsilon-acetyl), lysyl(N-epsilon-nicotinyl), norleucyl,norvalyl, D-norvalyl, N-methylnorvalyl, ornithyl(N-delta-acetyl),3-(3-pyridyl)alanyl, sarcosyl, seryl, D-seryl, N-methylseryl, threonyl,tryptyl, valyl, and N-methylvalyl;

Xaa₅ is selected from the group consisting of alanyl, alloisoleucyl,aspartyl, citrullyl, glutaminyl, isoleucyl, D-isoleucyl,N-methylisoleucyl, leucyl, D-leucyl, lysyl, lysyl(N-epsilon-acetyl),D-lysyl(N-epsilon-acetyl), norleucyl, norvalyl, phenylalanyl, prolyl,D-prolyl, and valyl;

Xaa₆ is selected from the group consisting of D-alloisoleucyl, arginyl,D-arginyl, citrullyl, histidyl, lysyl, lysyl(N-epsilon-isopropyl),ornithyl, and 3-(3-pyridyl)alanyl;

Xaa₇ is absent or selected from the group consisting ofN-methyl-D-alanyl, 2-aminobutyryl, 2-aminoisobutyryl, D-glutaminyl,homoprolyl, hydroxyprolyl, leucyl, phenylalanyl, prolyl, D-prolyl,threonyl, and D-valyl; and

Xaa₈ is selected from the group consisting of D-alanylamide,azaglycylamide, glycylamide, hydroxyl, D-lysyl(N-epsilon-acetyl)amide, agroup represented by the formula —NH—(CH₂)_(n)—CHR¹R²; and a grouprepresented by the formula —NHR³, wherein n is an integer from 0 to 8;R¹ is selected from the group consisting of hydrogen, alkyl,cycloalkenyl, and cycloalkyl; R² is selected from the group consistingof hydrogen, alkoxy, alkyl, aryl, cycloalkenyl, cycloalkyl, heterocycle,and hydroxyl, provided that when n is 0, R² is other than alkoxy orhydroxyl; and R³ is selected from the group consisting of hydrogen,cycloalkenyl, cycloalkyl, and hydroxyl; and

provided that when Xaa₆ is D-alloisoleucyl, Xaa₇ is threonyl and Xaa₈ ishydroxyl.

In a preferred embodiment, the present invention provides a compound offormula (II)Xaa₁-Xaa₂-Xaa₃-Xaa₄-Xaa₅-Xaa₆-Xaa₇-Xaa₈  (II),(SEQ ID NO:2)or a therapeutically acceptable salt thereof, wherein

Xaa₁ is absent or R—(CH₂)_(n)—C(O)—, wherein n is an integer from 0 to 8and R is selected from the group consisting of alkoxy, alkyl, amino,aryl, carboxyl, cycloalkenyl, cycloalkyl, and heterocycle;

Xaa₂ is selected from the group consisting of β-alanyl, D-alanyl,D-alloisoleucyl, D-allylglycyl, D-4-chlorophenylalanyl, D-citrullyl,D-3-cyanophenylalanyl, D-homophenylalanyl, D-homoseryl, isoleucyl,D-isoleucyl, D-leucyl, N-methyl-D-leucyl, D-norleucyl, D-norvalyl,D-penicillaminyl, D-phenylalanyl, D-prolyl, D-seryl, D-thienylalanyl,and D-threonyl;

Xaa₃ is selected from the group consisting of allothreonyl, aspartyl,glutaminyl, D-glutaminyl, N-methylglutaminyl, glycyl, histidyl,homoseryl, isoleucyl, lysyl(N-epsilon-acetyl), methionyl, seryl,N-methylseryl, threonyl, D-threonyl, tryptyl, tyrosyl, andtyrosyl(O-methyl);

Xaa₄ is selected from the group consisting of N-methylalanyl,allothreonyl, arginyl, glutaminyl, D-glutaminyl, glycyl, homoseryl,leucyl, lysyl(N-epsilon-acetyl), norleucyl, norvalyl, D-norvalyl,N-methylnorvalyl, ornithyl(N-delta-acetyl), 3-(3-pyridyl)alanyl,sarcosyl, seryl, N-methylseryl, threonyl, tryptyl, valyl andN-methylvalyl;

Xaa₅ is selected from the group consisting of alanyl, alloisoleucyl,aspartyl, citrullyl, glutaminyl, isoleucyl, D-isoleucyl,N-methylisoleucyl, leucyl, D-leucyl, lysyl, lysyl(N-epsilon-acetyl),D-lysyl(N-epsilon-acetyl), norleucyl, norvalyl, phenylalanyl, prolyl,and D-prolyl;

Xaa₆ is selected from the group consisting of arginyl, D-arginyl,citrullyl, histidyl, lysyl, lysyl(N-epsilon-isopropyl), ornithyl, and3-(3-pyridyl)alanyl;

Xaa₇ is absent or selected from the group consisting ofN-methyl-D-alanyl, 2-aminobutyryl, 2-aminoisobutyryl, D-glutaminyl,homoprolyl, hydroxyprolyl, leucyl, phenylalanyl, prolyl, D-prolyl, andD-valyl; and

Xaa₈ is selected from the group consisting of D-alanylamide,azaglycylamide, glycylamide, hydroxyl, D-lysyl(N-epsilon-acetyl)amide, agroup represented by the formula —NH—(CH₂)_(n)—CHR¹R²; and a grouprepresented by the formula —NHR³, wherein n is an integer from 0 to 8;R¹ is selected from the group consisting of hydrogen, alkyl,cycloalkenyl, and cycloalkyl; R² is selected from the group consistingof hydrogen, alkoxy, alkyl, aryl, cycloalkenyl, cycloalkyl, heterocycle,and hydroxyl, with the proviso that when n is 0, R² is other than alkoxyor hydroxyl; and R³ is selected from the group consisting of hydrogen,cycloalkenyl, cycloalkyl, and hydroxyl.

In a more preferred embodiment, the present invention provides acompound of formula (II), or a therapeutically acceptable salt thereof,wherein Xaa₂ is selected from the group consisting of β-alanyl,D-alloisoleucyl, D-4-chlorophenylalanyl, D-homophenylalanyl, D-leucyl,D-penicillaminyl, and D-prolyl; and Xaa₁, Xaa₃, Xaa₄, Xaa₅, Xaa₆, Xaa₇,and Xaa₈ are as described for formula (II).

In another more preferred embodiment, the present invention provides acompound of formula (II), or a therapeutically acceptable salt thereof,wherein Xaa₂ is D-isoleucyl, Xaa₃ is selected from the group consistingof allothreonyl, aspartyl, glutaminyl, lysyl(N-epsilon-acetyl),methionyl, seryl, and tyrosyl, and Xaa₁, Xaa₄, Xaa₅, Xaa₆, Xaa₇, andXaa₈ are as described for formula (II).

In another more preferred embodiment, the present invention provides acompound of formula (II), or a therapeutically acceptable salt thereof,wherein Xaa₂ is D-isoleucyl, Xaa₃ is threonyl, Xaa₄ is selected from thegroup consisting of arginyl, glutaminyl, D-glutaminyl, norleucyl,norvalyl, N-methylnorvalyl, seryl, and tryptyl, and Xaa₁, Xaa₅, Xaa₆,Xaa₇, and Xaa₈ are as described for formula (II).

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a compound of formula (II), or a therapeuticallyacceptable salt thereof, in combination with a therapeuticallyacceptable carrier.

In another embodiment, the present invention provides a method ofinhibiting angiogenesis in a mammal in recognized need of such treatmentcomprising administering to the mammal a therapeutically acceptableamount of a compound of formula (II) or a therapeutically acceptablesalt thereof.

In another embodiment, the present invention provides a method oftreating cancer in a mammal in recognized need of such treatmentcomprising administering to the mammal a therapeutically acceptableamount of a compound of formula (II) or a therapeutically acceptablesalt thereof.

In another preferred embodiment, the present invention provides acompound of formula (III)Xaa₁-Xaa₂-Xaa₃-Xaa₄-Xaa₅-Xaa₆-Xaa₇  (III),(SEQ ID NO:3)or a therapeutically acceptable salt thereof, wherein

Xaa₁ is absent or R—(CH₂)_(n)—C(O)—, wherein n is an integer from 0 to 8and R is selected from the group consisting of alkoxy, alkyl, amino,aryl, carboxyl, cycloalkenyl, cycloalkyl, and heterocycle;

Xaa₂ is selected from the group consisting of D-alanyl, D-alloisoleucyl,allothreonyl, allylglycyl, asparaginyl, aspartyl, glutaminyl,D-glutaminyl, glutamyl, N-methylglutamyl, glycyl, histidyl, homoseryl,D-homoseryl, isoleucyl, D-isoleucyl, lysyl(N-epsilon-acetyl), methionyl,D-methionyl, norleucyl, D-norleucyl, norvalyl, D-norvalyl, D-prolyl,sarcosyl, seryl, D-seryl, N-methylseryl, threonyl, D-threonyl, tryptyl,tyrosyl, and tyrosyl(O-methyl);

Xaa₃ is selected from the group consisting of N-methylalanyl,allothreonyl, arginyl, asparaginyl, D-asparaginyl, citrullyl,glutaminyl, D-glutaminyl, glutamyl, glycyl, homoseryl, leucyl, D-leucyl,lysyl(N-epsilon-acetyl), lysyl(N-epsilon-nicotinyl), norleucyl,norvalyl, D-norvalyl, N-methylnorvalyl, ornithyl(N-delta-acetyl),3-(3-pyridyl)alanyl, sarcosyl, seryl, D-seryl, N-methylseryl, threonyl,tryptyl, valyl, and N-methylvalyl;

Xaa₄ is selected from the group consisting of alanyl, alloisoleucyl,aspartyl, citrullyl, isoleucyl, D-isoleucyl, N-methylisoleucyl, leucyl,D-leucyl, lysyl, lysyl(N-epsilon-acetyl), D-lysyl(N-epsilon-acetyl),norvalyl, phenylalanyl, prolyl, D-prolyl, and valyl;

Xaa₅ is selected from the group consisting of D-alloisoleucyl, arginyl,D-arginyl, citrullyl, histidyl, lysyl, lysyl(N-epsilon-isopropyl),ornithyl, and 3-(3-pyridyl)alanyl;

Xaa₆ is absent or selected from the group consisting ofN-methyl-D-alanyl, 2-aminobutyryl, 2-aminoisobutyryl, D-glutaminyl,homoprolyl, hydroxyprolyl, leucyl, phenylalanyl, prolyl, D-prolyl,threonyl, and D-valyl; and

Xaa₇ is selected from the group consisting of D-alanylamide,azaglycylamide, glycylamide, hydroxyl, D-lysyl(N-epsilon-acetyl)amide, agroup represented by the formula —NH—(CH₂)_(n)—CHR¹R²; and a grouprepresented by the formula —NHR³, wherein n is an integer from 0 to 8;R¹ is selected from the group consisting of hydrogen, alkyl,cycloalkenyl, and cycloalkyl; R² is selected from the group consistingof hydrogen, alkoxy, alkyl, aryl, cycloalkenyl, cycloalkyl, heterocycle,and hydroxyl, with the proviso that when n is 0, R² is other than alkoxyor hydroxyl; and R³ is selected from the group consisting of hydrogen,cycloalkenyl, cycloalkyl, and hydroxyl;

provided that when Xaa₅ is D-alloisoleucyl, Xaa₆ is threonyl and Xaa₇ ishydroxyl.

In a more preferred embodiment, the present invention provides acompound of formula (III), or a therapeutically acceptable salt thereof,wherein Xaa₂ is selected from the group consisting of threonyl andD-threonyl, Xaa₃ is selected from the group consisting of norvalyl andD-norvalyl, Xaa₅ is arginyl, and Xaa₁, Xaa₄, Xaa₆, and Xaa₇ are asdefined for formula (II).

In another more preferred embodiment, the present invention provides acompound of formula (III), or a therapeutically acceptable salt thereof,wherein Xaa₂ is selected from the group consisting of allothreonyl,asparaginyl, aspartyl, homoseryl, sarcosyl, and tyrosyl, Xaa₃ isselected from the group consisting of norvalyl and D-norvalyl, Xaa₅ isarginyl, and Xaa₁, Xaa₄, Xaa₆, and Xaa₇ are as defined for formula(III).

In another more preferred embodiment, the present invention provides acompound of formula (III), or a therapeutically acceptable salt thereof,wherein Xaa₂ is selected from the group consisting of glutaminyl,glutamyl, N-methylglutamyl, lysyl(N-epsilon-acetyl), methionyl, seryl,and tryptyl, Xaa₃ is selected from the group consisting of norvalyl andD-norvalyl, Xaa₅ is arginyl, and Xaa₁, Xaa₄, Xaa₆, and Xaa₇ are asdefined for formula (III).

In another more preferred embodiment, the present invention provides acompound of formula (III), or a therapeutically acceptable salt thereof,wherein Xaa₃ is selected from the group consisting of glutaminyl andD-glutaminyl, Xaa₅ is arginyl, and Xaa₁, Xaa₂, Xaa₄, Xaa₆, and Xaa₇ areas defined for formula (III).

In another more preferred embodiment, the present invention provides acompound of formula (III), or a therapeutically acceptable salt thereof,wherein Xaa₃ is selected from the group consisting of seryl and D-seryl,Xaa₅ is arginyl, and Xaa₁, Xaa₂, Xaa₄, Xaa₆, and Xaa₇ are as defined forformula (III).

In another more preferred embodiment, the present invention provides acompound of formula (III), or a therapeutically acceptable salt thereof,wherein Xaa₃ is selected from the group consisting of arginyl,asparaginyl, D-asparaginyl, citrullyl, glutamyl, D-leucyl,lysyl(N-epsilon-acetyl), lysyl(N-epsilon-nicotinyl), norleucyl,N-methylnorvalyl, threonyl, and tryptyl, Xaa₅ is arginyl, and Xaa₁,Xaa₂, Xaa₄, Xaa₆, and Xaa₇ are as defined for formula (III).

In another more preferred embodiment, the present invention provides acompound of formula (III), or a therapeutically acceptable salt thereof,wherein Xaa₅ is selected from the group consisting of D-alloisoleucyl,citrullyl, lysyl(N-epsilon-isopropyl), ornithyl, and3-(3-pyridyl)alanyl, and Xaa₁, Xaa₂, Xaa₃, Xaa₄, Xaa₆, and Xaa₇ are asdefined for formula (III).

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a compound of formula (III), or a therapeuticallyacceptable salt thereof, in combination with a therapeuticallyacceptable carrier.

In another embodiment, the present invention provides a method ofinhibiting angiogenesis in a mammal in recognized need of such treatmentcomprising administering to the mammal a therapeutically acceptableamount of a compound of formula (III) or a therapeutically acceptablesalt thereof.

In another embodiment, the present invention provides a method oftreating cancer in a mammal in recognized need of such treatmentcomprising administering to the mammal a therapeutically acceptableamount of a compound of formula (III) or a therapeutically acceptablesalt thereof.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the singular forms “a”, “an”, and “the” include pluralreference unless the context clearly dictates otherwise.

As used in the present specification the following terms have themeanings indicated:

The term “alkoxy,” as used herein, represents an alkyl group attached tothe parent molecular moiety through an oxygen atom.

The term “alkyl,” as used herein, represents a monovalent group derivedfrom a straight or branched chain saturated hydrocarbon by the removalof a hydrogen atom. Preferred alkyl groups for the present invention arealkyl groups having from one to six carbon atoms (C₁–C₆ alkyl). Alkylgroups of one to three carbon atoms (C₁–C₃ alkyl) are more preferred forthe present invention.

The term “alkylcarbonyl,” as used herein, represents an alkyl groupattached to the parent molecular moiety through a carbonyl group.

The term “amino,” as used herein, represents —NR^(a)R^(b), wherein R^(a)and R^(b) are independently selected from the group consisting ofhydrogen, alkyl, and alkylcarbonyl.

The term “aryl,” as used herein, represents a phenyl group, or abicyclic or tricyclic fused ring system wherein one or more of the fusedrings is a phenyl group. Bicyclic fused ring systems are exemplified bya phenyl group fused to a cycloalkenyl group, as defined herein, acycloalkyl group, as defined herein, or another phenyl group. Tricyclicfused ring systems are exemplified by a bicyclic fused ring system fusedto a cycloalkenyl group, as defined herein, a cycloalkyl group, asdefined herein or another phenyl group. Representative examples of arylinclude, but are not limited to, anthracenyl, azulenyl, fluorenyl,indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl. The arylgroups of the present invention can be optionally substituted with one-,two, three, four, or five substituents independently selected from thegroup consisting of alkoxy, alkyl, carboxyl, halo, and hydroxyl.

The term “carbonyl,” as used herein, represents —C(O)—.

The term “carboxyl,” as used herein, represents —CO₂H.

The term “cycloalkenyl,” as used herein, refers to a non-aromatic cyclicor bicyclic ring system having three to ten carbon atoms and one tothree rings, wherein each five-membered ring has one double bond, eachsix-membered ring has one or two double bonds, each seven- andeight-membered ring has one to three double bonds, and each nine-toten-membered ring has one to four double bonds. Examples of cycloalkenylgroups include cyclohexenyl, octahydronaphthalenyl, norbornylenyl, andthe like. The cycloalkenyl groups of the present invention can beoptionally substituted with one, two, three, four, or five substituentsindependently selected from the group consisting of alkoxy, alkyl,carboxyl, halo, and hydroxyl.

The term “cycloalkyl,” as used herein, refers to a saturated monocyclic,bicyclic, or tricyclic hydrocarbon ring system having three to twelvecarbon atoms. Examples of cycloalkyl groups include cyclopropyl,cyclopentyl, bicyclo[3.1.1]heptyl, adamantyl, and the like. Thecycloalkyl groups of the present invention can be optionally substitutedwith one, two, three, four, or five substituents independently selectedfrom the group consisting of alkoxy, alkyl, carboxyl, halo, andhydroxyl.

The term “halo,” as used herein, represents F, Cl, Br, or I.

The term “heterocycle,” as used herein, refers to a five-, six-, orseven-membered ring containing one, two, or three heteroatomsindependently selected from the group consisting of nitrogen, oxygen,and sulfur. The five-membered ring has zero to two double bonds and thesix- and seven-membered rings have zero to three double bonds. The term“heterocycle” also includes bicyclic groups in which the heterocyclering is fused to an aryl group, as defined herein. The heterocyclegroups of the present invention can be attached through a carbon atom ora nitrogen atom in the group. Examples of heterocycles include, but arenot limited to, furyl, thienyl, pyrrolyl, pyrrolidinyl, oxazolyl,thiazolyl, imidazolyl, imidazolinyl, pyrazolyl, isoxazolyl,isothiazolyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,pyridinyl, indolyl, indolinyl, and benzothienyl. The heterocycle groupsof the present invention can be optionally substituted with one, two,three, or four substituents independently selected from the groupconsisting of alkoxy, alkyl, carboxyl, halo, and hydroxyl.

The term “hydroxyl,” as used herein, represents —OH.

The term “therapeutically acceptable salt,” as used herein, representssalts or zwitterionic forms of the compounds of the present inventionwhich are water or oil-soluble or dispersible, which are suitable fortreatment of diseases without undue toxicity, irritation, and allergicresponse; which are commensurate with a reasonable benefit/risk ratio,and which are effective for their intended use. The salts can beprepared during the final isolation and purification of the compounds orseparately by reacting an amino group with a suitable acid.Representative acid addition salts include acetate, adipate, alginate,citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,camphorate, camphorsulfonate, digluconate, glycerophosphate,hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethansulfonate, lactate, maleate,mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,3-phenylproprionate, picrate, pivalate, propionate, succinate, tartrate,trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate,para-toluenesulfonate, and undecanoate. Also, amino groups in thecompounds of the present invention can be quaternized with methyl,ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl,diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, andsteryl chlorides, bromides, and iodides; and benzyl and phenethylbromides. Examples of acids which can be employed to formtherapeutically acceptable addition salts include inorganic acids suchas hydrochloric, hydrobromic, sulfuric, and phosphoric, and organicacids such as oxalic, maleic, succinic, and citric.

Unless indicated otherwise by a “D” prefix, e.g., D-Ala or NMe-D-Ile,the stereochemistry of the α-carbon of the amino acids and aminoacylresidues in peptides described in this specification and the appendedclaims is the natural or “L” configuration. The Cahn-Ingold-Prelog “R”and “S” designations are used to specify the stereochemistry of chiralcenters in certain acyl substituents at the N-terminus of the peptidesof this invention. The designation “R,S” is meant to indicate a racemicmixture of the two enantiomeric forms.

All peptide sequences are written according to the generally acceptedconvention whereby the α-N-terminal amino acid residue is on the leftand the α-C-terminal is on the right. As used herein, the term“α-N-terminus” refers to the free α-amino group of an amino acid in apeptide, and the term “α-C-terminus” refers to the free α-carboxylicacid terminus of an amino acid in a peptide.

For the most part, the names on naturally occurring and non-naturallyoccurring aminoacyl residues used herein follow the naming conventionssuggested by the IUPAC Commission on the Nomenclature of Organicchemistry and the IUPAC-IUB Commission on Biochemical Nomenclature. Tothe extent that the names and abbreviations of amino acids and aminoacylresidues employed in this specification and appended claims differ fromthose suggestions, they will be made clear to the reader. Someabbreviations useful in describing the invention are defined below inthe following Table 1.

TABLE 1 Abbreviation Definition N-Ac N-acetyl Ala alanyl bAla β-alanylAlaNH₂ alanylamide aIle alloisoleucyl alloThr allothreonylalloThr(O-tBu) allothreonyl(O-t-butyl) AllylGly allylglycyl Arg arginylArg(Pmc) arginyl(N^(G)-2,2,5,7,8-pentamethylchroman- 6-sulfonyl)Fmoc-Arg(Pbf)-OH N-Fmoc-N^(G)-(2,2,4,6,7-pentamethyldihydrobenzofuran-5- sulfonyl)arginine Asn asparaginylAsn(Trt) asparaginyl(trityl) Asp aspartyl Asp(O-tBu) aspartyl(O-t-butyl)Cit citrullyl Fmoc 9-fluorenylmethyloxycarbonyl Gln glutaminyl Gln(Trt)glutaminyl(trityl) Glu glutamyl Glu(O-tBu) glutamyl(O-t-butyl) NMeGluN-methylglutamyl Gly glycyl His histidyl His(Trt) histidyl(trityl) Hphehomophenylalanyl Hser homoseryl Hser(Trt) homoseryl(trityl) Ileisoleucyl Leu leucyl Lys(Ac) lysyl(N-epsilon-acetyl) Lys(Boc)lysyl(N-epsilon-t-butoxycarbonyl) Lys(Isp) lysyl(N-epsilon-isopropyl)Lys(Nic) lysyl(N-epsilon-nicotinyl) Met methionyl N-3MevN-3-methylvaleryl N-(6MeNic) 6-methylnicotinyl Nle norleucyl Nvanorvalyl NMeNva N-methylnorvalyl Orn ornithyl Orn(Ac)ornithyl(N-delta-acetyl) Orn(Boc) ornithyl(t-butoxycarbonyl) 3-Pal3-(3-pyridyl)alanyl Pen penicillaminyl Pen(Trt) penicillaminyl(trityl)4ClPhe 4-chlorophenylalanyl Phe phenylalanyl Pro prolyl ProNHCH(CH₃)₂prolylisopropylamide ProNHCH₂CH₃ prolylethylamide 3-Pal3-(3-pyridyl)alanyl Sar sarcosyl Ser seryl Ser(O-tBu) seryl(O-t-butyl)Thr threonyl Thr(O-tBu) threonyl(O-t-butyl) Trp tryptyl Trp(Boc)tryptyl(N-t-butoxycarbonyl) Tyr tyrosyl Tyr(O-tBu) tyrosyl(O-t-butyl)Val valylCompositions

The compounds of the invention, including but not limited to thosespecified in the examples, possess anti-angiogenic activity. Asangiogenesis inhibitors, such compounds are useful in the treatment ofboth primary and metastatic solid tumors, including carcinomas ofbreast, colon, rectum, lung, oropharynx, hypopharynx, esophagus,stomach, pancreas, liver, gallbladder and bile ducts, small intestine,urinary tract (including kidney, bladder and urothelium), female genitaltract (including cervix, uterus, and ovaries as well as choriocarcinomaand gestational trophoblastic disease), male genital tract (includingprostate, seminal vesicles, testes and germ cell tumors), endocrineglands (including the thyroid, adrenal, and pituitary glands), and skin,as well as hemangiomas, melanomas, sarcomas (including those arisingfrom bone and soft tissues as well as Kaposi's sarcoma) and tumors ofthe brain, nerves, eyes, and meninges (including astrocytomas, gliomas,glioblastomas, retinoblastomas, neuromas, neuroblastomas, Schwannomas,and meningiomas). Such compounds may also be useful in treating solidtumors arising from hematopoietic malignancies such as leukemias (i.e.,chloromas, plasmacytomas and the plaques and tumors of mycosisfungicides and cutaneous T-cell lymphoma/leukemia) as well as in thetreatment of lymphomas (both Hodgkin's and non-Hodgkin's lymphomas). Inaddition, these compounds may be useful in the prevention of metastasesfrom the tumors described above either when used alone or in combinationwith radiotherapy and/or other chemotherapeutic agents.

Further uses include the treatment and prophylaxis of autoimmunediseases such as rheumatoid, immune and degenerative arthritis; variousocular diseases such as diabetic retinopathy, retinopathy ofprematurity, corneal graft rejection, retrolental fibroplasia,neovascular glaucoma, rubeosis, retinal neovascularization due tomacular degeneration, hypoxia, angiogenesis in the eye associated withinfection or surgical intervention, and other abnormalneovascularization conditions of the eye; skin diseases such aspsoriasis; blood vessel diseases such as hemagiomas, and capillaryproliferation within atherosclerotic plaques; Osler-Webber Syndrome;myocardial angiogenesis; plaque neovascularization; telangiectasia;hemophiliac joints; angiofibroma; and wound granulation. Other usesinclude the treatment of diseases characterized by excessive or abnormalstimulation of endothelial cells, including not limited to intestinaladhesions, Crohn's disease, atherosclerosis, scleroderma, andhypertrophic scars, i.e., keloids. Another use is as a birth controlagent, by inhibiting ovulation and establishment of the placenta. Thecompounds of the invention are also useful in the treatment of diseasesthat have angiogenesis as a pathologic consequence such as cat scratchdisease (Rochele minutesalia quintosa) and ulcers (Helicobacter pylori).The compounds of the invention are also useful to reduce bleeding byadministration prior to surgery, especially for the treatment ofresectable tumors.

The compounds of the invention may be used in combination with othercompositions and procedures for the treatment of diseases. For example,a tumor may be treated conventionally with surgery, radiation orchemotherapy combined with a peptide of the present invention and then apeptide of the present invention may be subsequently administered to thepatient to extend the dormancy of micrometastases and to stabilize andinhibit the growth of any residual primary tumor. Additionally, thecompounds of the invention may be combined with pharmaceuticallyacceptable excipients, and optionally sustained-release matrices, suchas biodegradable polymers, to form therapeutic compositions.

A sustained-release matrix, as used herein, is a matrix made ofmaterials, usually polymers, which are degradable by enzymatic oracid-base hydrolysis or by dissolution. Once inserted into the body, thematrix is acted upon by enzymes and body fluids. A sustained-releasematrix desirably is chosen from biocompatible materials such asliposomes, polylactides (polylactic acid), polyglycolide (polymer ofglycolic acid), polylactide co-glycolide (copolymers of lactic acid andglycolic acid) polyanhydrides, poly(ortho)esters, polypeptides,hyaluronic acid, collagen, chondroitin sulfate, carboxylic acids, fattyacids, phospholipids, polysaccharides, nucleic acids, polyamino acids,amino acids such as phenylalanine, tyrosine, isoleucine,polynucleotides, polyvinyl propylene, polyvinylpyrrolidone and silicone.A preferred biodegradable matrix is a matrix of one of eitherpolylactide, polyglycolide, or polylactide co-glycolide (co-polymers oflactic acid and glycolic acid).

When used in the above or other treatments, a therapeutically effectiveamount of one of the compounds of the present invention may be employedin pure form or, where such forms exist, in therapeutically acceptablesalt form. By a “therapeutically effective amount” of the compound ofthe invention is meant a sufficient amount of the compound to treat anangiogenic disease, (for example, to limit tumor growth or to slow orblock tumor metastasis) at a reasonable benefit/risk ratio applicable toany medical treatment. It will be understood, however, that the totaldaily usage of the compounds and compositions of the present inventionwill be decided by the attending physician within the scope of soundmedical judgment. The specific therapeutically effective dose level forany particular patient will depend upon a variety of factors includingthe disorder being treated and the severity of the disorder; activity ofthe specific compound employed; the specific composition employed, theage, body weight, general health, sex and diet of the patient; the timeof administration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination with the specific compound employed; and like factors wellknown in the medical arts. For example, it is well within the skill ofthe art to start doses of the compound at levels lower than thoserequired to achieve the desired therapeutic effect and to graduallyincrease the dosage until the desired effect is achieved.

Alternatively, a compound of the present invention may be administeredas pharmaceutical compositions containing the compound of interest incombination with one or more pharmaceutically acceptable excipients. Apharmaceutically acceptable carrier or excipient refers to a non-toxicsolid, semi-solid or liquid filler, diluent, encapsulating material orformulation auxiliary of any type. The compositions may be administeredparenterally, intracisternally, intravaginally, intraperitoneally,topically (as by powders, ointments, drops or transdermal patch),rectally, or bucally. The term “parenteral” as used herein refers tomodes of administration which include intravenous, intramuscular,intraperitoneal, intrasternal, subcutaneous and intraarticular injectionand infusion.

Pharmaceutical compositions for parenteral injection comprisepharmaceutically-acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions, as well as sterile powders forreconstitution into sterile injectable solutions or dispersions justprior to use. Examples of suitable aqueous and nonaqueous carriers,diluents, solvents or vehicles include water, ethanol, polyols (such asglycerol, propylene glycol, polyethylene glycol, and the like),carboxymethylcellulose and suitable mixtures thereof, vegetable oils(such as olive oil), and injectable organic esters such as ethyl oleate.Proper fluidity may be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservative,wetting agents, emulsifying agents, and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents such as sugars, sodium chloride,and the like. Prolonged absorption of the injectable pharmaceutical formmay be brought about by the inclusion of agents which delay absorption,such as aluminum monostearate and gelatin.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide,poly(orthoesters), poly(anhydrides), and (poly)glycols, such as PEG.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Depot injectable formulations are also prepared by entrapping the drugin liposomes or microemulsions which are compatible with body tissues.

The injectable formulations may be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Topical administration includes administration to the skin or mucosa,including surfaces of the lung and eye. Compositions for topicaladministration, including those for inhalation, may be prepared as a drypowder which may be pressurized or non-pressurized. In non-pressurizedpowder compositions, the active ingredient in finely divided form may beused in admixture with a larger-sized pharmaceutically-acceptable inertcarrier comprising particles having a size, for example, of up to 100micrometers in diameter. Suitable inert carriers include sugars such aslactose. Desirably, at least 95% by weight of the particles of theactive ingredient have an effective particle size in the range of 0.01to 10 micrometers.

Alternatively, the composition may be pressurized and contain acompressed gas, such as nitrogen or a liquefied gas propellant. Theliquefied propellant medium and indeed the total composition ispreferably such that the active ingredient does not dissolve therein toany substantial extent. The pressurized composition may also contain asurface active agent, such as a liquid or solid non-ionic surface activeagent or may be a solid anionic surface active agent. It is preferred touse the solid anionic surface active agent in the form of a sodium salt.

A further form of topical administration is to the eye. A compound ofthe invention is delivered in a pharmaceutically acceptable ophthalmicvehicle, such that the compound is maintained in contact with the ocularsurface for a sufficient time period to allow the compound to penetratethe corneal and internal regions of the eye, as for example the anteriorchamber, posterior chamber, vitreous body, aqueous humor, vitreoushumor, cornea, iris/ciliary, lens, choroid/retina and sclera. Thepharmaceutically-acceptable ophthalmic vehicle may, for example, be anointment, vegetable oil or an encapsulating material. Alternatively, thecompounds of the invention may be injected directly into the vitreousand aqueous humour.

Compositions for rectal or vaginal administration are preferablysuppositories which may be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature liquid at body temperature and therefore melt in therectum or vaginal cavity and release the active compound.

Compounds of the present invention may also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals that are dispersed inan aqueous medium. Any non-toxic, physiologically-acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients, and the like. The preferred lipids are the phospholipids andthe phosphatidyl cholines (lecithins), both natural and synthetic.Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they may also be used in combination withone or more agents which are conventionally administered to patients fortreating angiogenic diseases. For example, the compounds of theinvention are effective over the short term to make tumors moresensitive to traditional cytotoxic therapies such as chemicals andradiation. The compounds of the invention also enhance the effectivenessof existing cytotoxic adjuvant anti-cancer therapies. The compounds ofthe invention may also be combined with other antiangiogenic agents toenhance their effectiveness, or combined with other antiangiogenicagents and administered together with other cytotoxic agents. Inparticular, when used in the treatment of solid tumors, compounds of theinvention may be administered with IL-12, retinoids, interferons,angiostatin, endostatin, thalidomide, thrombospondin-1,thrombospondin-2, captopryl, angioinhibins, TNP-470, pentosanpolysulfate, platelet factor 4, LM-609, SU-5416, CM-101, Tecogalan,plasminogen-K-5, vasostatin, vitaxin, vasculostatin, squalamine,marimastat or other MMP inhibitors, anti-neoplastic agents such as alphainteferon, COMP (cyclophosphamide, vincristine, methotrexate andprednisone), etoposide, mBACOD (methortrexate, bleomycin, doxorubicin,cyclophosphamide, vincristine and dexamethasone), PRO-MACE/MOPP(prednisone, methotrexate (w/leucovin rescue), doxorubicin,cyclophosphamide, cisplatin, taxol, etoposide/mechlorethamine,vincristine, prednisone and procarbazine), vincristine, vinblastine, andthe like as well as with radiation.

Total daily dose of the compositions of the invention to be administeredto a human or other mammal host in single or divided doses may be inamounts, for example, from 0.0001 to 300 mg/kg body weight daily andmore usually 1 to 300 mg/kg body weight.

It will be understood that agents which can be combined with thecompound of the present invention for the inhibition, treatment orprophylaxis of angiogenic diseases are not limited to those listedabove, include in principle any agents useful for the treatment orprophylaxis of angiogenic diseases.

Determination of Biological Activity

In vitro Assay for Angiogenic Activity

The human microvascular endothelial (HMVEC) migration assay was runaccording to the procedure of S. S. Tolsma, O. V. Volpert, D. J. Good,W. F. Frazier, P. J. Polyerini and N. Bouck, J. Cell Biol. 1993, 122,497–511.

The HMVEC migration assay was carried out using Human MicrovascularEndothelial Cells-Dermal (single donor) and Human MicrovascularEndothelial Cells, (neonatal). The HMVEC cells were starved overnight inDME containing 0.01% bovine serum albumin (BSA). Cells were thenharvested with trypsin and resuspended in DME with 0.01% BSA at aconcentration of 1.5×10⁶ cells per mL. Cells were added to the bottom ofa 48 well modified Boyden chamber (Nucleopore Corporation, Cabin John,Md.). The chamber was assembled and inverted, and cells were allowed toattach for 2 hours at 37° C. to polycarbonate chemotaxis membranes (5 μmpore size) that had been soaked in 0.01% gelatin overnight and dried.The chamber was then reinverted, and test substances (total volume of 50μL), including activators, 15 ng/mL bFGF/VEGF, were added to the wellsof the upper chamber. The apparatus was incubated for 4 hours at 37° C.Membranes were recovered, fixed and stained (Diff Quick, FisherScientific) and the number of cells that had migrated to the upperchamber per 3 high power fields counted. Background migration to DME+0.1BSA was subtracted and the data reported as the number of cells migratedper 10 high power fields (400×) or, when results from multipleexperiments were combined, as the percent inhibition of migrationcompared to a positive control.

Representative compounds described in Examples 1 to 154 inhibited humanendothelial cell migration in the above assay by at least 55% whentested at a concentration of 10 nM. More preferred compounds inhibitedhuman endothelial cell migration by approximately 80% to 98% when testedat a concentration of 1 nM, and most preferred compounds inhibited humanendothelial cell migration by approximately 55% to 70% when tested at aconcentration of 0.01 nM. As shown by these results, the compounds ofthe present invention demonstrate enhanced potency as compared topreviously described antiangiogenic peptides.

Synthesis of the Peptides

This invention is intended to encompass compounds having formula (I)when prepared by synthetic processes or by metabolic processes.Preparation of the compounds of the invention by metabolic processesinclude those occurring in the human or animal body (in vivo) orprocesses occurring in vitro.

The polypeptides of the present invention may be synthesized by manytechniques that are known to those skilled in the art. For solid phasepeptide synthesis, a summary of the many techniques may be found in J.M. Stewart and J. D. Young, Solid Phase Peptide Synthesis, W. H. FreemanCo. (San Francisco), 1963 and J. Meienhofer, Hormonal Proteins andPeptides, vol. 2, p. 46, Academic Press (New York), 1973. For classicalsolution synthesis see G. Schroder and K. Lupke, The Peptides, vol. 1,Academic Press (New York), 1965.

Reagents, resins, amino acids, and amino acid derivatives arecommercially available and can be purchased from chem-ImpexInternational, Inc. (Wood Dale, Ill., U.S.A.) or Calbiochem-NovabiochemCorp. (San Diego, Calif., U.S.A.) unless otherwise noted herein.

In general, these methods comprise the sequential addition of one ormore amino acids or suitably protected amino acids to a growing peptidechain. Normally, either the amino or carboxyl group of the first aminoacid is protected by a suitable protecting group. The protected orderivatized amino acid can then be either attached to an inert solidsupport or utilized in solution by adding the next amino acid in thesequence having the complimentary (amino or carboxyl) group suitablyprotected, under conditions suitable for forming the amide linkage. Theprotecting group is then removed from this newly added amino acidresidue and the next amino acid (suitably protected) is then added, andso forth. After all the desired amino acids have been linked in theproper sequence, any remaining protecting groups (and any solid support)are removed sequentially or concurrently, to afford the finalpolypeptide. By simple modification of this general procedure, it ispossible to add more than one amino acid at a time to a growing chain,for example, by coupling (under conditions which do not racemize chiralcenters) a protected tripeptide with a properly protected dipeptide toform, after deprotection, a pentapeptide.

A particularly preferred method of preparing compounds of the presentinvention involves solid phase peptide synthesis. In this particularlypreferred method the α-amino function is protected by an acid or basesensitive group. Such protecting groups should have the properties ofbeing stable to the conditions of peptide linkage formation, while beingreadily removable without destruction of the growing peptide chain orracemization of any of the chiral centers contained therein. Suitableprotecting groups are 9-fluorenylmethyloxycarbonyl (Fmoc),t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz),biphenylisopropyl-oxycarbonyl, t-amyloxycarbonyl, isobornyloxycarbonyl,(α,α)-dimethyl-3,5-dimethoxybenzyloxycarbonyl, O-nitrophenylsulfenyl,2-cyano-t-butyloxycarbonyl, and the like. The9-fluorenylmethyloxycarbonyl (Fmoc) protecting group is preferred.

Particularly preferred side chain protecting groups are: for arginine:N^(G)-2,2,5,7,8-pentamethylchroman-6-sulfonyl (Pmc), and2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf); for asparagine:trityl (Trt); for aspartic acid: t-butyl (t-Bu); for glutamic acid:tert-butyl ester (O-tBu); for glutamine: trityl (Trt); forN-methylglutamine: t-butyl (t-Bu); for homoserine: trityl (Trt); forhistidine: trityl (Trt); for lysine: t-butoxycarbonyl (Boc); forornithyl: t-butoxycarbonyl (Boc), for penicillamine: trityl (Trt); forserine: t-butyl (t-Bu); for threonine and allothreonine: t-butyl (t-Bu);for tryptophan: t-butoxycarbonyl (Boc); and for tyrosine: t-butyl(t-Bu).

In the solid phase peptide synthesis method, the C-terminal amino acidis attached to a suitable solid support or resin. Suitable solidsupports useful for the above synthesis are those materials which areinert to the reagents and reaction conditions of the stepwisecondensation-deprotection reactions, as well as being insoluble in themedia used. The preferred solid support for synthesis of C-terminalcarboxyl peptides is Sieber amide resin or Sieber ethylamide resin. Thepreferred solid support for C-terminal amide peptides is Sieberethylamide resin available from Novabiochem Corporation.

The C-terminal amino acid is coupled to the resin by means of a couplingmediated by N,N′-dicyclohexylcarbodiimide (DCC),N,N′-diisopropylcarbodiimide (DIC),[O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate] (HATU), orO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate(HBTU), with or without 4-dimethylaminopyridine (DMAP),1-hydroxybenzotriazole (HOBT), N-methylmorpholine (NMM),benzotriazol-1-yloxy-tris(dimethylamino)phosphonium-hexafluorophosphate(BOP) or bis(2-oxo-3-oxazolidinyl)phosphine chloride (BOPCl), for about1 to about 24 hours at a temperature of between 10° C. and 50° C. in asolvent such as dichloromethane or DMF.

When the solid support is Sieber amide or Sieber ethylamide resin, theFmoc group is cleaved with a secondary amine, preferably piperidine,prior to coupling with the C-terminal amino acid as described above. Thepreferred reagents used in the coupling to the deprotected4-(2′,4′-dimethoxyphenyl-Fmoc-aminomethyl)phenoxyacetamidoethyl resinare O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate(HBTU, 1 equiv.) with 1-hydroxybenzotriazole (HOBT, 1 equiv.), or[O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate] (HATU, 1 equiv.) with N-methylmorpholine (1 equiv.)in DMF.

The coupling of successive protected amino acids can be carried out inan automatic polypeptide synthesizer as is well known in the art. In apreferred embodiment, the α-amino function in the amino acids of thegrowing peptide chain are protected with Fmoc. The removal of the Fmocprotecting group from the N-terminal side of the growing peptide isaccomplished by treatment with a secondary amine, preferably piperidine.Each protected amino acid is then introduced in about 3-fold molarexcess and the coupling is preferably carried out in DMF. The couplingagent is normallyO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate(HBTU, 1 equiv.) or[O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate] (HATU, 1 equiv.) in the presence ofN-methylmorpholine (NMM, 1 equiv.).

At the end of the solid phase synthesis, the polypeptide is removed fromthe resin and deprotected, either in succession or in a singleoperation. Removal of the polypeptide and deprotection can beaccomplished in a single operation by treating the resin-boundpolypeptide with a cleavage reagent, for example trifluoroacetic acidcontaining thianisole, water, or ethanedithiol.

In cases where the C-terminus of the polypeptide is an alkylamide, theresin is cleaved by aminolysis with an alkylamine. Alternatively, thepeptide may be removed by transesterification, e.g., with methanol,followed by aminolysis or by direct transamidation. The protectedpeptide may be purified at this point or taken to the next stepdirectly. The removal of the side chain protecting groups isaccomplished using the cleavage cocktail described above.

The fully deprotected peptide is purified by a sequence ofchromatographic steps employing any or all of the following types: ionexchange on a weakly basic resin in the acetate form; hydrophobicadsorption chromatography on underivatized polystyrene-divinylbenzene(for example, AMBERLITE® XAD); silica gel adsorption chromatography; ionexchange chromatography on carboxymethylcellulose; partitionchromatography, e.g., on SEPHADEX® G-25, LH-20 or countercurrentdistribution; high performance liquid chromatography (HPLC), especiallyreverse-phase HPLC on octyl- or octadecylsilyl-silica bonded phasecolumn packing.

The foregoing may be better understood in light of the examples whichare meant to describe compounds and process which can be carried out inaccordance with the invention and are not intended as a limitation onthe scope of the invention in any way.

Abbreviations which have been used the following examples are: DMF forN,N-dimethylformamide; HBTU forO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate; NMMfor N-methylmorpholine; TFA for trifluoroacetic acid; NMP forN-methylpyrrolidinone; and HATU for[O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate].

EXAMPLE 1 N-Ac-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

In the reaction vessel of a Rainin peptide synthesizer was placedFmoc-Pro-Sieber ethylamide resin (0.25 g, 0.4 mmol/g loading). The resinwas solvated with DMF and amino acids were coupled sequentiallyaccording to the following synthetic cycle:

-   (1) 3×1.5 minute washes with DMF;-   (2) 2×15 minute deprotections using 20% piperidine;-   (3) 6×3 minute washes with DMF;-   (4) addition of amino acid;-   (5) activation of amino acid with 0.4 M HBTU/NMM and coupling;-   (6) 3×1.5 minute washes with DMF.

The protected amino acids were coupled to the resin in the followingorder:

Protected Amino Acid Coupling time Fmoc-Arg(Pmc) 30 minutes Fmoc-Ile 30minutes Fmoc-Nva 30 minutes Fmoc-Thr(O-tBu) 30 minutes Fmoc-D-Ile 30minutes acetic acid 30 minutes

Upon completion of the synthesis the peptide was cleaved from the resinusing a mixture of (95:2.5:2.5) TFA/anisole/water for 3 hours. Thepeptide solution was concentrated under vacuum and then precipitatedwith diethyl ether and collected by filtration. The crude peptide waspurified by HPLC using a C-18 column and a solvent mixture varying over50 minutes in a gradient from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions were lyophilized to provideN-Ac-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=3.38 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 767 (M+H)⁺; AminoAcid Anal.: 2.06 Ile; 0.58 Thr; 1.01 Nva; 0.98 Arg; 1.04 Pro.

EXAMPLE 2 N-Ac-D-aIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-aIle forFmoc-D-Ile in Example 1. After workup the crude peptide was purified byHPLC using a C-18 column and a solvent mixture varying over 50 minutesin a gradient from 5% to 100% acetonitrile/water containing 0.01% TFA.The pure fractions were lyophilized to provideN-Ac-D-aIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=2.52 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 767 (M+H)⁺; AminoAcid Anal.: 2.11 Ile; 0.43 Thr; 0.99 Nva; 1.03 Arg; 1.02 Pro.

EXAMPLE 3 N-Ac-D-Ile-alloThr-Nva-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-alloThr(O-tBu) forFmoc-Thr(O-tBu) in Example 1. After workup the crude peptide waspurified by HPLC using a C-18 column and a solvent mixture varying over50 minutes in a gradient from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions were lyophilized to provideN-Ac-D-Ile-alloThr-Nva-Ile-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=2.56 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 767 (M+H)⁺; AminoAcid Anal.: 2.02 Ile; 0.51 Thr; 0.96 Nva; 1.03 Arg; 1.07 Pro.

EXAMPLE 4 N-Ac-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-Gln(Trt) forFmoc-Nva in Example 1. After workup the crude peptide was purified byHPLC using a C-18 column and a solvent mixture varying over 50 minutesin a gradient from 5% to 100% acetonitrile/water containing 0.01% TFA.The pure fractions were lyophilized to provideN-Ac-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=1.79 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 796 (M+H)⁺; AminoAcid Anal.: 2.05 Ile; 0.44 Thr; 0.94 Glu; 1.02 Arg; 0.99 Pro.

EXAMPLE 5 N-Ac-D-aIle-Ser-Ser-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-aIle forFmoc-D-Ile and Fmoc-Ser(O-tBu) for both Fmoc-Thr(O-tBu) and Fmoc-Nva inExample 1. After workup the crude peptide was purified by HPLC using aC-18 column and a solvent mixture varying over 50 minutes in a gradientfrom 5% to 100% acetonitrile/water containing 0.01% TFA. The purefractions were lyophilized to provideN-Ac-D-aIle-Ser-Ser-Ile-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=1.39 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 741 (M+H)⁺; AminoAcid Anal.: 2.13 Ile; 0.48 Ser; 1.02 Arg; 1.04 Pro.

EXAMPLE 6 N-Ac-D-aIle-Thr-Ser-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-aIle forFmoc-D-Ile and Fmoc-Ser(O-tBu) for Fmoc-Nva in Example 1. After workupthe crude peptide was purified by HPLC using a C-18 column and a solventmixture varying over 50 minutes in a gradient from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-D-aIle-Thr-Ser-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=1.73 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 755 (M+H)⁺; Amino Acid Anal.: 2.10 Ile; 0.49 Thr; 0.21 Ser;1.04 Arg; 1.02 Pro.

EXAMPLE 7 N-Ac-D-aIle-Tyr-Nva-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-aIle forFmoc-D-Ile and Fmoc-Tyr(O-tBu) for Fmoc-Thr(O-tBu) in Example 1. Afterworkup the crude peptide was purified by HPLC using a C-18 column and asolvent mixture varying over 50 minutes in a gradient from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-D-aIle-Tyr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.89 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 829 (M+H)⁺; Amino Acid Anal.: 2.06 Ile; 0.99 Tyr; 1.03 Nva;1.01 Arg; 1.00 Pro.

EXAMPLE 8 N-Ac-D-aIle-Ser-Thr-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-aIle forFmoc-D-Ile, Fmoc-Ser(O-tBu) for Fmoc-Thr(O-tBu) and Fmoc-Thr(O-tBu) forFmoc-Nva in Example 1. After workup the crude peptide was purified byHPLC using a C-18 column and a solvent mixture varying over 50 minutesin a gradient from 5% to 100% acetonitrile/water containing 0.01% TFA.The pure fractions were lyophilized to provideN-Ac-D-aIle-Ser-Thr-Ile-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=1.40 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 755 (M+H)⁺; AminoAcid Anal.: 2.10 Ile; 0.19 Ser; 0.52 Thr; 1.02 Arg; 1.01 Pro.

EXAMPLE 9 N-(6MeNic)-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting 6-methylnicotinic acidfor acetic acid in Example 1. After workup the crude peptide waspurified by HPLC using a C-18 column and a solvent mixture varying over50 minutes in a gradient from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions were lyophilized to provideN-(6-Me-Nicotinyl)-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=1.96 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 844 (M+H)⁺; Amino Acid Anal.: 2.06 Ile; 0.50 Thr; 1.02 Nva;1.04 Arg; 0.99 Pro.

EXAMPLE 10 N-Ac-D-Pro-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-Pro forFmoc-D-Ile in Example 1. After workup the crude peptide was purified byHPLC using a C-18 column and a solvent mixture varying over 50 minutesin a gradient from 5% to 100% acetonitrile/water containing 0.01% TFA.The pure fractions were lyophilized to provideN-Ac-D-Pro-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=1.62 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 751 (M+H)⁺; AminoAcid Anal.: 1.01 Ile; 0.49 Thr; 0.98 Nva; 1.00 Arg; 2.08 Pro.

EXAMPLE 11 N-Ac-D-Ile-Thr-Nva-Pro-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-Pro for Fmoc-Ilein Example 1. After workup the crude peptide was purified by HPLC usinga C-18 column and a solvent mixture varying over 50 minutes in agradient from 5% to 100% acetonitrile/water containing 0.01% TFA. Thepure fractions were lyophilized to provideN-Ac-D-Ile-Thr-Nva-Pro-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=1.49 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 751 (M+H)⁺; AminoAcid Anal.: 1.01 Ile; 0.54 Thr; 1.00 Nva; 1.00 Arg; 2.03 Pro.

EXAMPLE 12 N-Ac-D-Ile-Thr-Nva-Ile-Arg-D-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-Pro-Sieberethylamide resin for Fmoc-Pro-Sieber ethylamide resin in Example 1.After workup the crude peptide was purified by HPLC using a C-18 columnand a solvent mixture varying over 50 minutes in a gradient from 5% to100% acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-D-Ile-Thr-Nva-Ile-Arg-D-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.59 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/c 767 (M+H)⁺; Amino Acid Anal.: 2.04 Ile; 0.47 Thr; 1.02 Nva;1.06 Arg; 1.01 Pro.

EXAMPLE 13 N-Ac-D-Ile-Ser-Gln-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-Ser(O-tBu) forFmoc-Thr(O-tBu) and Fmoc-Gln(Trt) for Fmoc-Nva in Example 1. Afterworkup the crude peptide was purified by HPLC using a C-18 column and asolvent mixture varying over 50 minutes in a gradient from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-D-Ile-Ser-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=1.28 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 782 (M+H)⁺; Amino Acid Anal.: 2.07 Ile; 0.22 Ser; 0.97 Glu;1.03 Arg; 1.04 Pro.

EXAMPLE 14 N-Ac-D-Ile-Thr-Ser-Ile-Arg-Pro-D-AlaNH₂

The desired product was prepared by substituting Fmoc-Ser(O-tBu) forFmoc-Nva and Fmoc-D-Ala-Sieber amide resin for Fmoc-Pro-Sieberethylamide resin and adding a coupling with Fmoc-Pro before the couplingwith Fmoc-Arg(Pmc) in Example 1. After workup the crude peptide waspurified by HPLC using a C-18 column and a solvent mixture varying over50 minutes in a gradient from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions were lyophilized to provideN-Ac-D-Ile-Thr-Ser-Ile-Arg-Pro-D-AlaNH₂ as the trifluoroacetate salt:R_(t)=1.35 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 798 (M+H)⁺; AminoAcid Anal.: 2.02 Ile; 0.43 Thr; 0.24 Ser; 1.01 Arg; 0.99 Pro; 1.02 Ala.

EXAMPLE 15 N-Ac-D-Ile-Ser-Nva-Ile-Arg-Pro-D-AlaNH₂

The desired product was prepared by substituting Fmoc-Ser(O-tBu) forFmoc-Thr(O-tBu) and Fmoc-D-Ala-Sieber amide resin for Fmoc-Pro-Sieberethylamide resin and adding a coupling with Fmoc-Pro before the couplingwith Fmoc-Arg(Pmc) in Example 1. After workup the crude peptide waspurified by HPLC using a C-18 column and a solvent mixture varying over50 minutes in a gradient from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions were lyophilized to provideN-Ac-D-Ile-Ser-Nva-Ile-Arg-Pro-D-AlaNH₂ as the trifluoroacetate salt:R_(t)=2.60 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 796 (M+H)⁺; AminoAcid Anal.: 2.03 Ile; 0.19 Ser; 1.00 Nva; 1.01 Arg; 0.98 Pro; 1.02 Ala.

EXAMPLE 16 N-Ac-D-Ile-Ser-Gln-D-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-Ser(O-tBu) forFmoc-Thr(O-tBu), Fmoc-Gln(Trt) for Fmoc-Nva and Fmoc-D-Ile for Fmoc-Ilein Example 1. After workup the crude peptide was purified by HPLC usinga C-18 column and a solvent mixture varying over 50 minutes in agradient from 5% to 100% acetonitrile/water containing 0.01% TFA. Thepure fractions were lyophilized to provideN-Ac-D-Ile-Ser-Gln-D-Ile-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=1.28 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 782 (M+H)⁺; AminoAcid Anal.: 2.05 Ile; 0.29 Ser; 1.02 Glu; 1.03 Arg; 1.02 Pro.

EXAMPLE 17 N-Ac-D-Ile-Gln-Nva-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-Gln(Trt) forFmoc-Thr(O-tBu) in Example 1. After workup the crude peptide waspurified by HPLC using a C-18 column and a solvent mixture varying over50 minutes in a gradient from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions were lyophilized to provideN-Ac-D-Ile-Gln-Nva-Ile-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=1.45 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 794 (M+H)⁺; AminoAcid Anal.: 2.10 Ile; 1.01 Glu; 1.02 Nva; 0.99 Arg; 0.98 Pro.

EXAMPLE 18 N-Ac-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH₂

The desired product was prepared by substituting Fmoc-D-Ala-Sieber amideresin for Fmoc-Pro-Sieber ethylamide resin and adding a coupling withFmoc-Pro before the coupling with Fmoc-Arg(Pmc) in Example 1. Afterworkup the crude peptide was purified by HPLC using a C-18 column and asolvent mixture varying over 50 minutes in a gradient from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH₂ as thetrifluoroacetate salt: R_(t)=2.10 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 10 (M+H)⁺; Amino Acid Anal.: 2.10 Ile; 0.49 Thr; 0.99 Nva;1.00 Arg; 0.98 Pro; 1.02 Ala.

EXAMPLE 19 N-Ac-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-Leu forFmoc-D-Ile in Example 1. After workup the crude peptide was purified byHPLC using a C-18 column and a solvent mixture varying over 50 minutesin a gradient from 5% to 100% acetonitrile/water containing 0.01% TFA.The pure fractions were lyophilized to provideN-Ac-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=2.57 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 767 (M+H)⁺; AminoAcid Anal.: 1.01 Leu; 0.51 Thr; 1.00 Nva; 1.04 Ile; 1.02 Arg; 1.04 Pro.

EXAMPLE 20 N-Ac-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-Leu forFmoc-D-Ile and Fmoc-Ser(O-tBu) for Fmoc-Thr(O-tBu) in Example 1. Afterworkup the crude peptide was purified by HPLC using a C-18 column and asolvent mixture varying over 50 minutes in a gradient from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.50 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 753 (M+H)⁺; Amino Acid Anal.: 1.01 Leu; 0.23 Ser; 1.03 Nva;1.02 Ile; 1.02 Arg; 0.99 Pro.

EXAMPLE 21 N-Ac-D-Ile-Thr-Nva-D-Leu-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-Leu for Fmoc-Ilein Example 1. After workup the crude peptide was purified by HPLC usinga C-18 column and a solvent mixture varying over 50 minutes in agradient from 5% to 100% acetonitrile/water containing 0.01% TFA. Thepure fractions were lyophilized to provideN-Ac-D-Ile-Thr-Nva-D-Leu-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=2.71 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 767 (M+H)⁺; AminoAcid Anal.: 1.02 Ile; 0.55 Thr; 1.01 Nva; 1.00 Leu; 1.01 Arg; 1.01 Pro.

EXAMPLE 22 N-Ac-D-Ile-Thr-Nva-D-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-Ile for Fmoc-Ilein Example 1. After workup the crude peptide was purified by HPLC usinga C-18 column and a solvent mixture varying over 50 minutes in agradient from 5% to 100% acetonitrile/water containing 0.01% TFA. Thepure fractions were lyophilized to provideN-Ac-D-Ile-Thr-Nva-D-Ile-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=2.61 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/c 767 (M+H)⁺; AminoAcid Anal.: 2.04 Ile; 0.42 Thr; 1.02 Nva; 1.00 Arg; 1.03 Pro.

EXAMPLE 23 N-Ac-D-Ile-Tyr-Nva-D-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-Tyr(O-tBu) forFmoc-Thr(O-tBu) and Fmoc-D-Ile for Fmoc-Ile in Example 1. After workupthe crude peptide was purified by HPLC using a C-18 column and a solventmixture varying over 50 minutes in a gradient from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-D-Ile-Tyr-Nva-D-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.94 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 829 (M+H)⁺; Amino Acid Anal.: 2.09 Ile; 0.96 Tyr; 1.03 Nva;0.97 Arg; 1.01 Pro.

EXAMPLE 24 N-Ac-D-Ile-Thr-Trp-D-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-Trp(Boc) forFmoc-Nva and Fmoc-D-Ile for Fmoc-Ile in Example 1. After workup thecrude peptide was purified by HPLC using a C-18 column and a solventmixture varying over 50 minutes in a gradient from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-D-Ile-Thr-Trp-D-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.17 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 854 (M+H)⁺.

EXAMPLE 25 N-Ac-D-aIle-Thr-Trp-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-aIle forFmoc-D-Ile and Fmoc-Trp(Boc) for Fmoc-Nva in Example 1. After workup thecrude peptide was purified by HPLC using a C-18 column and a solventmixture varying over 50 minutes in a gradient from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-D-aIle-Thr-Trp-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.06 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 854 (M+H)⁺.

EXAMPLE 26 N-Ac-D-Ile-Thr-Trp-Ile-Arg-Pro-D-AlaNH₂

The desired product was prepared by substituting Fmoc-Trp(Boc) forFmoc-Nva and Fmoc-D-Ala-Sieber amide resin for Fmoc-Pro-Sieberethylamide resin and adding a coupling with Fmoc-Pro before the couplingwith Fmoc-Arg(Pmc) in Example 1. After workup the crude peptide waspurified by HPLC using a C-18 column and a solvent mixture varying over50 minutes in a gradient from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions were lyophilized to provideN-Ac-D-Ile-Thr-Trp-Ile-Arg-Pro-D-AlaNH₂ as the trifluoroacetate salt:R_(t)=2.97 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 897 (M+H)⁺.

EXAMPLE 27 N-Ac-D-Ile-Thr-Nva-Ile-Arg-Pro-D-Lys(Ac)NH₂

The desired product was prepared by substitutingFmoc-D-Lys(Ac)-Sieber-amide resin for Fmoc-Pro-Sieber ethylamide resinand adding a coupling with Fmoc-Pro before the coupling withFmoc-Arg(Pmc) in Example 1. After workup the crude peptide was purifiedby HPLC using a C-18 column and a solvent mixture varying over 50minutes in a gradient from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions were lyophilized to provideN-Ac-D-Ile-Thr-Nva-Ile-Arg-Pro-D-Lys(Ac)NH₂ as the trifluoroacetatesalt: R_(t)=2.32 minutes (gradient varying over 10 minutes from 20% to80% acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 909 (M+H)⁺.

EXAMPLE 28 N-Ac-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂

The desired product was prepared by substituting Fmoc-Gln(Trt) forFmoc-Nva and Fmoc-D-Ala-Sieber amide resin for Fmoc-Pro-Sieberethylamide resin and adding a coupling with Fmoc-Pro before the couplingwith Fmoc-Arg(Pmc) in Example 1. After workup the crude peptide waspurified by HPLC using a C-18 column and a solvent mixture varying over50 minutes in a gradient from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions were lyophilized to provideN-Ac-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂ as the trifluoroacetate salt:R_(t)=1.34 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 839 (M+H)⁺.

EXAMPLE 29 N-Ac-D-Ile-Thr-Nva-D-Lys(Ac)-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-Lys(Ac) forFmoc-Ile in Example 1. After workup the crude peptide was purified byHPLC using a C-18 column and a solvent mixture varying over 50 minutesin a gradient from 5% to 100% acetonitrile/water containing 0.01% TFA.The pure fractions were lyophilized to provideN-Ac-D-Ile-Thr-Nva-D-Lys(Ac)-Arg-ProNHCH₂CH₃ as the trifluoroacetatesalt: R_(t)=1.58 minutes (gradient varying over 10 minutes from 20% to80% acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 824 (M+H)⁺.

EXAMPLE 30 N-Ac-D-Ile-Thr-Nva-Lys(Ac)-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-Lys(Ac) forFmoc-Ile in Example 1. After workup the crude peptide was purified byHPLC using a C-18 column and a solvent mixture varying over 50 minutesin a gradient from 5% to 100% acetonitrile/water containing 0.01% TFA.The pure fractions were lyophilized to provideN-Ac-D-Ile-Thr-Nva-Lys(Ac)-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=1.51 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 824 (M+H)⁺.

EXAMPLE 31 N-Ac-D-Ile-Lys(Ac)-Nva-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-Lys(Ac) forFmoc-Thr(O-tBu) in Example 1. After workup the crude peptide waspurified by HPLC using a C-18 column and a solvent mixture varying over50 minutes in a gradient from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions were lyophilized to provideN-Ac-D-Ile-Lys(Ac)-Nva-Ile-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=2.51 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 836 (M+H)⁺.

EXAMPLE 32 N-Ac-D-Ile-Thr-Nva-Ile-His-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-His(Trt) forFmoc-Arg(Pmc) in Example 1. After workup the crude peptide was purifiedby HPLC using a C-18 column and a solvent mixture varying over 50minutes in a gradient from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions were lyophilized to provideN-Ac-D-Ile-Thr-Nva-Ile-His-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=2.45 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 748 (M+H)⁺.

EXAMPLE 33 N-Ac-D-Hphe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-Hphe forFmoc-D-Ile in Example 1. After workup the crude peptide was purified byHPLC using a C-18 column and a solvent mixture varying over 50 minutesin a gradient from 5% to 100% acetonitrile/water containing 0.01% TFA.The pure fractions were lyophilized to provideN-Ac-D-Hphe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=3.12 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 815 (M+H)⁺.

EXAMPLE 34 N-Ac-D-4ClPhe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-4ClPhe forFmoc-D-Ile in Example 1. After workup the crude peptide was purified byHPLC using a C-18 column and a solvent mixture varying over 50 minutesin a gradient from 5% to 100% acetonitrile/water containing 0.01% TFA.The pure fractions were lyophilized to provideN-Ac-D-4ClPhe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=3.28 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 835 (M+H)⁺.

EXAMPLE 35 N-Ac-D-Pen-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-Pen(Trt) forFmoc-D-Ile in Example 1. After workup the crude peptide was purified byHPLC using a C-18 column and a solvent mixture varying over 50 minutesin a gradient from 5% to 100% acetonitrile/water containing 0.01% TFA.The pure fractions were lyophilized to provideN-Ac-D-Pen-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=2.41 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 785 (M+H)⁺.

EXAMPLE 36 N-Ac-D-Ile-Met-Nva-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-Met forFmoc-Thr(O-tBu) in Example 1. After workup the crude peptide waspurified by HPLC using a C-18 column and a solvent mixture varying over50 minutes in a gradient from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions were lyophilized to provideN-Ac-D-Ile-Met-Nva-Ile-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=3.11 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 797 (M+H)⁺.

EXAMPLE 37 N-Ac-D-Ile-Asp-Nva-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-Asp(O-tBu) forFmoc-Thr(O-tBu) in Example 1. After workup the crude peptide waspurified by HPLC using a C-18 column and a solvent mixture varying over50 minutes in a gradient from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions were lyophilized to provideN-Ac-D-Ile-Asp-Nva-Ile-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=2.32 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 781 (M+H)⁺.

EXAMPLE 38 N-Ac-D-Ile-Thr-Nva-Ile-3-Pal-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-3-Pal forFmoc-Arg(Pmc) in Example 1. After workup the crude peptide was purifiedby HPLC using a C-18 column and a solvent mixture varying over 50minutes in a gradient from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions were lyophilized to provideN-Ac-D-Ile-Thr-Nva-Ile-3-Pal-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=2.45 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 759 (M+H)⁺.

EXAMPLE 39 N-Ac-D-Ile-Thr-Nva-Ile-D-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-Arg(Pmc) forFmoc-Arg(Pmc) in Example 1. After workup the crude peptide was purifiedby HPLC using a C-18 column and a solvent mixture varying over 50minutes in a gradient from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions were lyophilized to provideN-Ac-D-Ile-Thr-Nva-Ile-D-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=2.71 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 767 (M+H)⁺.

EXAMPLE 40 N-Ac-D-Ile-Thr-Nle-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-Nle for Fmoc-Nvain Example 1. After workup the crude peptide was purified by HPLC usinga C-18 column and a solvent mixture varying over 50 minutes in agradient from 5% to 100% acetonitrile/water containing 0.01% TFA. Thepure fractions were lyophilized to provideN-Ac-D-Ile-Thr-Nle-Ile-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=2.82 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 781 (M+H)⁺.

EXAMPLE 41 N-Ac-D-Ile-Thr-D-Gln-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-Gln(Trt) forFmoc-Nva in Example 1. After workup the crude peptide was purified byHPLC using a C-18 column and a solvent mixture varying over 50 minutesin a gradient from 5% to 100% acetonitrile/water containing 0.01% TFA.The pure fractions were lyophilized to provideN-Ac-D-Ile-Thr-D-Gln-Ile-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=1.60 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 796 (M+H)⁺.

EXAMPLE 42 N-Ac-D-Ile-alloThr-Nva-Pro-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-alloThr(O-tBu) forFmoc-Thr(O-tBu) and Fmoc-Pro for Fmoc-Ile in Example 1. After workup thecrude peptide was purified by HPLC using a C-18 column and a solventmixture varying over 50 minutes in a gradient from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-D-Ile-alloThr-Nva-Pro-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=1.52 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 751 (M+H)⁺.

EXAMPLE 43 N-Ac-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ (SEQ ID NO:4)

In the reaction vessel of a Rainin peptide synthesizer Fmoc-Pro-Sieberethylamide resin (0.25 g, 0.4 mmol/g loading) was placed. The resin wassolvated with DMF and amino acids were coupled sequentially according tothe following synthetic cycle:

-   (1) 3×1.5 minute washes with DMF;-   (2) 2×15 minute deprotections using 20% piperidine;-   (3) 6×3 minute washes with DMF;-   (4) addition of amino acid;-   (5) activation of amino acid with 0.4 M HBTU/NMM and coupling;-   (6) 3×1.5 minute washes with DMF.

The protected amino acids were coupled to the resin in the followingorder:

Protected Amino Acid Coupling time Fmoc-Arg(Pmc) 30 minutes Fmoc-Ile 30minutes Fmoc-Nva 30 minutes Fmoc-Thr(O-tBu) 30 minutes acetic acid 30minutes

Upon completion of the synthesis the peptide was cleaved from the resinusing a mixture of (95:2.5:2.5) TFA/anisole/water for 3 hours. Thepeptide solution was concentrated under vacuum and then precipitatedwith diethyl ether and collected by filtration. The crude peptide waspurified by HPLC using a C-18 column and with a solvent mixture varyingover 50 minutes from 5% to 100% acetonitrile/water containing 0.01% TFA.The pure fractions were lyophilized to provideN-Ac-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=1.16 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 654 (M+H)⁺; AminoAcid Anal.: 0.49 Thr; 1.02 Nva; 0.99 Ile; 1.01 Arg; 1.04 Pro.

EXAMPLE 44 N-Ac-alloThr-Nva-Ile-Arg-ProNHCH₂CH₃ (SEQ ID NO:5)

The desired product was prepared by substituting Fmoc-alloThr(O-tBu) forFmoc-Thr(O-tBu) in Example 43. After workup the crude peptide waspurified by HPLC using a C-18 column and a solvent system varying ingradient from 5% to 100% acetonitrile/water containing 0.01% TFA over 50minutes. The pure fractions were lyophilized to provideN-Ac-alloThr-Nva-Ile-Arg-ProNHCH₂CH₃ as the trifluoracetate salt:R_(t)=1.07 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 654 (M+H)⁺; AminoAcid Anal.: 0.57 Thr; 1.00 Nva; 1.02 Ile; 0.98 Arg; 1.04 Pro.

EXAMPLE 45 N-Ac-Thr-Gln-Ile-Arg-ProNHCH₂CH₃ (SEQ ID NO:6)

The desired product was prepared by substituting Fmoc-Gln(Trt) forFmoc-Nva in Example 43. After workup the crude peptide was purified byHPLC using a C-18 column and a solvent system varying in gradient over50 minutes from 5% to 100% acetonitrile/water containing 0.01% TFA. Thepure fractions were lyophilized to provideN-Ac-Thr-Gln-Ile-Arg-ProNHCH₂CH₃ as the trifluoracetate salt: R_(t)=1.01minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 683.5 (M+H)⁺;Amino Acid Anal.: 0.49 Thr; 1.01 Glu; 0.98 Ile; 1.05 Arg; 1.00 Pro.

EXAMPLE 46 N-(6MeNic)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ (SEQ ID NO:7)

The desired product was prepared by substituting 6-methylnicotinic acidfor acetic acid in Example 43. After workup the crude peptide waspurified by HPLC using a C-18 column and a solvent system varying ingradient over 50 minutes from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions were lyophilized to provideN(6MeNic)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as the trifluoracetate salt:R_(t)=0.94 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 731.5 (M+H)⁺;Amino Acid Anal.: 0.51 Thr; 1.00 Nva; 1.01 Ile; 1.10 Arg; 1.03 Pro.

EXAMPLE 47 N-Ac-Ser-Ser-Ile-Arg-ProNHCH₂CH₃ (SEQ ID NO:8)

The desired product was prepared by substituting Fmoc-Ser(O-tBu) forFmoc-Thr(O-tBu) and Fmoc-Nva in Example 43. After workup the crudepeptide was purified by HPLC using a C-18 column and a solvent systemvarying in gradient over 50 minutes from 5% to 100% acetonitrile/watercontaining 0.01% TFA. The pure fractions were lyophilized to provideN-Ac-Ser-Ser-Ile-Arg-ProNHCH₂CH₃ as the trifluoracetate salt: R_(t)=3.34minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 628.3 (M+H)⁺;Amino Acid Anal.: 0.43 Ser; 0.96 Ile; 1.00 Arg; 1.04 Pro.

EXAMPLE 48 N-Ac-Thr-Ser-Ile-Arg-ProNHCH₂CH₃ (SEQ ID NO:9)

The desired product was prepared by substituting Fmoc-Ser(O-tBu) forFmoc-Nva in Example 43. After workup the crude peptide was purified byHPLC using a C-18 column and a solvent system varying in gradient over50 minutes from 5% to 100% acetonitrile/water containing 0.01% TFA. Thepure fractions were lyophilized to provideN-Ac-Thr-Ser-Ile-Arg-ProNHCH₂CH₃ as the trifluoracetate salt: R_(t)=3.52minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 642.3 (M+H)⁺;Amino Acid Anal.: 0.55 Thr; 0.23 Ser; 0.96 Ile; 0.98 Arg; 1.04 Pro.

EXAMPLE 49 N-Ac-Thr-Nva-Ile-Arg-Pro-D-AlaNH₂

The desired product was prepared by substituting Fmoc-D-Ala-Sieber amideresin for Fmoc-Pro-Sieber ethylamide resin and adding a coupling withFmoc-Pro before the coupling with Fmoc-Arg(Pmc) in Example 43. Afterworkup the crude peptide was purified by HPLC using a C-18 column and asolvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-Thr-Nva-Ile-Arg-Pro-D-AlaNH₂ as thetrifluoracetate salt: R_(t)=3.94 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 697.3 (M+H)⁺; Amino Acid Anal.: 0.56 Thr; 0.92 Nva; 0.97 Ile;0.85 Arg; 1.09 Pro; 1.09 Ala.

EXAMPLE 50 N-Ac-Thr-Nva-D-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-Ile for Fmoc-Ilein Example 43. After workup the crude peptide was purified by HPLC usinga C-18 column and a solvent system varying in gradient over 50 minutesfrom 5% to 100% acetonitrile/water containing 0.01% TFA. The purefractions were lyophilized to provide N-Ac-Thr-Nva-D-Ile-Arg-ProNHCH₂CH₃as the trifluoracetate salt: R_(t)=4.59 minutes (gradient varying over10 minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 654.4 (M+H)⁺; Amino Acid Anal.: 0.51 Thr; 0.84 Nva; 1.03 Ile;0.97 Arg; 1.01 Pro.

EXAMPLE 51 N-Ac-Thr-NMeNva-Ile-Arg-ProNHCH₂CH₃ (SEQ ID NO: 10)

The desired product was prepared by substituting Fmoc-NMeNva forFmoc-Nva and using HATU as the activator in the Fmoc-NMeNva coupling inExample 43. After workup the crude peptide was purified by HPLC using aC-18 column and a solvent system varying in gradient over 50 minutesfrom 5% to 100% acetonitrile/water containing 0.01% TFA. The purefractions were lyophilized to provideN-Ac-Thr-NMeNva-Ile-Arg-ProNHCH₂CH₃ as the trifluoracetate salt:R_(t)=4.305 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 668.4 (M+H)⁺;Amino Acid Anal.: 0.22 Thr; 1.01 Ile; 0.95 Arg; 1.03 Pro.

EXAMPLE 52 N-Ac-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂

The desired product was prepared by substituting Fmoc-Gln(Trt) forFmoc-Nva, Fmoc-D-Ala-Sieber amide resin for Fmoc-Pro-Sieber ethylamideresin, and by adding a coupling with Fmoc-Pro before the coupling withFmoc-Arg(Pmc) in Example 43. After workup the crude peptide was purifiedby HPLC using a C-18 column and a solvent system varying in gradientover 50 minutes from 5% to 100% acetonitrile/water containing 0.01% TFA.The pure fractions were lyophilized to provideN-Ac-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂ as the trifluoracetate salt:R_(t)=3.375 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 726.4 (M+H)⁺;Amino Acid Anal.: 0.51 Thr; 0.55 Glu; 0.96 Ile; 0.82 Arg; 1.11 Pro; 1.12Ala.

EXAMPLE 53 N-Ac-Tyr-Nva-Ile-Arg-ProNHCH₂CH₃ (SEQ ID NO: 11)

The desired product was prepared by substituting Fmoc-Tyr(O-tBu) forFmoc-Thr(O-tBu) in Example 43. After workup the crude peptide waspurified by HPLC using a C-18 column and a solvent system varying ingradient from 5% to 100% acetonitrile/water containing 0.01% TFA. Thepure fractions were lyophilized to provideN-Ac-Tyr-Nva-Ile-Arg-ProNHCH₂CH₃ as the trifluoracetate salt:R_(t)=4.845 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 716.4 (M+H)⁺;Amino Acid Anal.: 0.94 Tyr; 0.85 Nva; 0.96 Ile; 1.02 Arg; 1.02 Pro.

EXAMPLE 54 N-Ac-Ser-Gln-Ile-Arg-ProNHCH₂CH₃ (SEQ ID NO:12)

The desired product was prepared by substituting Fmoc-Ser(O-tBu) forFmoc-Thr(O-tBu) and Fmoc-Gln(Trt) for Fmoc-Nva in Example 43. Afterworkup the crude peptide was purified by HPLC using a C-18 column and asolvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-Ser-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoracetate salt: R_(t)=3.377 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 669.3 (M+H)⁺; Amino Acid Anal.: 0.14 Ser; 0.79 Glu; 0.93 Ile;0.98 Arg; 1.04 Pro.

EXAMPLE 55 N-Ac-Thr-Nva-Lys(Ac)-Arg-ProNHCH₂CH₃ (SEQ ID NO:13)

The desired product was prepared by substituting Fmoc-Lys(Ac) forFmoc-Ile in Example 43. After workup the crude peptide was purified byHPLC using a C-18 column and a solvent system varying in gradient over50 minutes from 5% to 100% acetonitrile/water containing 0.01% TFA. Thepure fractions were lyophilized to provideN-Ac-Thr-Nva-Lys(Ac)-Arg-ProNHCH₂CH₃ as the trifluoracetate salt:R_(t)=3.556 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 711.4 (M+H)⁺;Amino Acid Anal.: 0.52 Thr; 0.84 Nva; 1.02 Lys; 0.97 Arg; 1.01 Pro.

EXAMPLE 56 N-Ac-Ser-Thr-Ile-Arg-ProNHCH₂CH₃ (SEQ ID NO:14)

The desired product was prepared by substituting Fmoc-Ser(O-tBu) forFmoc-Thr(O-tBu) and Fmoc-Thr(O-tBu) for Fmoc-Nva in Example 43. Afterworkup the crude peptide was purified by HPLC using a C-18 column and asolvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-Ser-Thr-Ile-Arg-ProNHCH₂CH₃ as thetrifluoracetate salt: R_(t)=3.388 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 642.3 (M+H)⁺; Amino Acid Anal.: 0.43 Thr; 0.19 Ser; 0.98 Ile;0.97 Arg; 1.06 Pro.

EXAMPLE 57 N-Ac-Tyr-Nva-D-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-Tyr(O-tBu) forFmoc-Thr(O-tBu) and Fmoc-D-Ile for Fmoc-Ile in Example 43. After workupthe crude peptide was purified by HPLC using a C-18 column and a solventsystem varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-Tyr-Nva-D-Ile-Arg-ProNHCH₂CH₃ as thetrifluoracetate salt: R_(t)=5.103 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 716.4 (M+H)⁺; Amino Acid Anal.: 0.94 Tyr; 0.85 Nva; 1.00 Ile;1.04 Arg; 1.02 Pro.

EXAMPLE 58 N-Ac-NMeGlu-Nva-Ile-Arg-ProNHCH₂CH₃ (SEQ ID NO: 15)

The desired product was prepared by substituting Fmoc-NMeGlu(t-Bu) forFmoc-Thr(O-tBu) and using HATU as activator in the Fmoc-NMeGlu(t-Bu)coupling in Example 43. After workup the crude peptide was purified byHPLC using a C-18 column and a solvent system varying in gradient over50 minutes from 5% to 100% acetonitrile/water containing 0.01% TFA. Thepure fractions were lyophilized to provideN-Ac-NMeGlu-Nva-Ile-Arg-ProNHCH₂CH₃ as the trifluoracetate salt:R_(t)=4.51 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 696.4 (M+H)⁺.

EXAMPLE 59 N-Ac-Met-Nva-Ile-Arg-ProNHCH₂CH₃ (SEQ ID NO: 16)

The desired product was prepared by substituting Fmoc-Met forFmoc-Thr(O-tBu) in Example 43. After workup the crude peptide waspurified by HPLC using a C-18 column and a solvent system varying ingradient over 50 minutes from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions were lyophilized to provideN-Ac-Met-Nva-Ile-Arg-ProNHCH₂CH₃ as the trifluoracetate salt:R_(t)=4.913 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 684.4 (M+H)⁺;Amino Acid Anal.: 0.91 Met; 0.90 Nva; 1.01 Ile; 1.03 Arg; 1.05 Pro.

EXAMPLE 60 N-Ac-Lys(Ac)-Nva-Ile-Arg-ProNHCH₂CH₃ (SEQ ID NO: 17)

The desired product was prepared by substituting Fmoc-Lys(Ac) forFmoc-Thr(O-tBu) in Example 43. After workup the crude peptide waspurified by HPLC using a C-18 column and a solvent system varying ingradient over 50 minutes from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions were lyophilized to provideN-Ac-Lys(Ac)-Nva-Ile-Arg-ProNHCH₂CH₃ as the trifluoracetate salt:R_(t)=4.328 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 723.5 (M+H)⁺;Amino Acid Anal.: 1.20 Lys; 0.89 Nva; 1.02 Ile; 0.97 Arg; 1.00 Pro.

EXAMPLE 61 N-Ac-Gln-Nva-Ile-Arg-ProNHCH₂CH₃ (SEQ ID NO: 18)

The desired product was prepared by substituting Fmoc-Gln(Trt) forFmoc-Thr(O-tBu) in Example 43. After workup the crude peptide waspurified by HPLC using a C-18 column and a solvent system varying ingradient over 50 minutes from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions were lyophilized to provideN-Ac-Gln-Nva-Ile-Arg-ProNHCH₂CH₃ as the trifluoracetate salt:R_(t)=3.993 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 681.4 (M+H)⁺;Amino Acid Anal.: 1.01 Glu; 0.90 Nva; 1.01 Ile; 0.97 Arg; 1.01 Pro.

EXAMPLE 62 N-Ac-alloThr-Ser-Ile-Arg-ProNHCH₂CH₃ (SEQ ID NO: 19)

The desired product was prepared by substituting Fmoc-alloThr(O-tBu) forFmoc-Thr(O-tBu) and Fmoc-Ser(O-tBu) for Fmoc-Nva in Example 43. Afterworkup the crude peptide was purified by HPLC using a C-18 column and asolvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-alloThr-Ser-Ile-Arg-ProNHCH₂CH₃ as thetrifluoracetate salt: R_(t)=3.507 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 642.3 (M+H)⁺; Amino Acid Anal.: 0.40 Thr; 0.09 Ser; 1.00 Ile;0.96 Arg; 1.05 Pro.

EXAMPLE 63 N-Ac-Thr-Nva-Ile-Arg-D-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-Pro-Sieberethylamide resin for Fmoc-Pro-Sieber amide resin in Example 43. Afterworkup the crude peptide was purified by HPLC using a C-18 column and asolvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-Thr-Nva-Ile-Arg-D-ProNHCH₂CH₃ as thetrifluoracetate salt: R_(t)=4.232 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 654.3 (M+H)⁺; Amino Acid Anal.: 0.39 Thr; 0.91 Nva; 1.01 Ile;0.98 Arg; 1.01 Pro.

EXAMPLE 64 N-Ac-alloThr-Nva-Pro-Arg-ProNHCH₂CH₃ (SEQ ID NO:20)

The desired product was prepared by substituting Fmoc-alloThr(O-tBu) forFmoc-Thr(O-tBu) and Fmoc-Pro for Fmoc-Ile in Example 43. After workupthe crude peptide was purified by HPLC using a C-18 column and a solventsystem varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-alloThr-Nva-Pro-Arg-ProNHCH₂CH₃ as thetrifluoracetate salt: R_(t)=3.586 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 638.3 (M+H)⁺; Amino Acid Anal.: 0.43 Thr; 0.88 Nva; 1.00 Arg;2.00 Pro.

EXAMPLE 65 N-Ac-Trp-Nva-Ile-Arg-ProNHCH₂CH₃ (SEQ ID NO:21)

The desired product was prepared by substituting Fmoc-Trp(Boc) forFmoc-Thr(O-tBu) in Example 43. After workup the crude peptide waspurified by HPLC using a C-18 column and a solvent system varying ingradient over 50 minutes from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions were lyophilized to provideN-Ac-Trp-Nva-Ile-Arg-ProNHCH₂CH₃ as the trifluoracetate salt:R_(t)=5.861 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 739.5 (M+H)⁺;Amino Acid Anal.: 0.22 Trp; 0.90 Nva; 0.95 Ile; 1.03 Arg; 1.03 Pro.

EXAMPLE 66 N-Ac-Thr-Nle-Ile-Arg-ProNHCH₂CH₃ (SEQ ID NO:22)

The desired product was prepared by substituting Fmoc-Nle for Fmoc-Nvain Example 43. After workup the crude peptide was purified by HPLC usinga C-18 column and a solvent system varying in gradient over 50 minutesfrom 5% to 100% acetonitrile/water containing 0.01% TFA. The purefractions were lyophilized to provide N-Ac-Thr-Nle-Ile-Arg-ProNHCH₂CH₃as the trifluoracetate salt: R_(t)=4.544 minutes (gradient varying over10 minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 668.4 (M+H)⁺; Amino Acid Anal.: 0.41 Thr; 1.01 Ile; 0.99 Arg;1.00 Pro.

EXAMPLE 67 N-Ac-Thr-D-Nva-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-Nva for Fmoc-Nvain Example 43. After workup the crude peptide was purified by HPLC usinga C-18 column and a solvent system varying in gradient over 50 minutesfrom 5% to 100% acetonitrile/water containing 0.01% TFA. The purefractions were lyophilized to provide N-Ac-Thr-D-Nva-Ile-Arg-ProNHCH₂CH₃as the trifluoracetate salt: R_(t)=4.373 minutes (gradient varying over10 minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 654.4 (M+H)⁺; Amino Acid Anal.: 0.40 Thr; 0.89 Nva; 1.03 Ile;0.98 Arg; 1.00 Pro.

EXAMPLE 68 N-Ac-Thr-Trp-Ile-Arg-Pro-D-AlaNH₂

The desired product was prepared by substituting Fmoc-D-Ala-Sieber amidefor Fmoc-Pro-Sieber ethylamide and Fmoc-Trp(Boc) for Fmoc-Nva and addinga coupling with Fmoc-Pro before the coupling with Fmoc-Arg(Pmc) inExample 43. After workup the crude peptide was purified by HPLC using aC-18 column and a solvent system varying in gradient over 50 minutesfrom 5% to 100% acetonitrile/water containing 0.01% TFA. The purefractions were lyophilized to provide N-Ac-Thr-Trp-Ile-Arg-Pro-D-AlaNH₂as the trifluoracetate salt: R_(t)=4.927 minutes (gradient varying over10 minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 784.5 (M+H)⁺; Amino Acid Anal.: 0.39 Thr; 0.10 Trp; 1.04 Ile;0.91 Arg; 1.03 Pro; 1.02 Ala.

EXAMPLE 69 N-Ac-Thr-Ser-Ile-Arg-Pro-D-AlaNH₂

The desired product was prepared by substituting Fmoc-D-Ala-Sieber amideresin for Fmoc-Pro-Sieber ethylamide resin and Fmoc-Ser(O-tBu) forFmoc-Nva and adding a coupling with Fmoc-Pro before the coupling withFmoc-Arg(Pmc) in Example 43. After workup the crude peptide was purifiedby HPLC using a C-18 column and a solvent system varying in gradientover 50 minutes from 5% to 100% acetonitrile/water containing 0.01% TFA.The pure fractions were lyophilized to provideN-Ac-Thr-Ser-Ile-Arg-Pro-D-AlaNH₂ as the trifluoracetate salt:R_(t)=3.322 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 685.4 (M+H)⁺;Amino Acid Anal.: 0.37 Thr; 0.10 Ser; 1.01 Ile; 0.92 Arg; 1.07 Pro; 1.01Ala.

EXAMPLE 70 N-Ac-Thr-D-Gln-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-Gln(Trt) forFmoc-Nva in Example 43. After workup the crude peptide was purified byHPLC using a C-18 column and a solvent system varying in gradient over50 minutes from 5% to 100% acetonitrile/water containing 0.01% TFA. Thepure fractions were lyophilized to provideN-Ac-Thr-D-Gln-Ile-Arg-ProNHCH₂CH₃ as the trifluoracetate salt:R_(t)=3.292 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 683.4 (M+H)⁺.

EXAMPLE 71 N-Ac-Ser-Ser-Ile-Arg-Pro-D-AlaNH₂

The desired product was prepared by substituting Fmoc-D-Ala-Sieber amideresin for Fmoc-Pro-Sieber ethyl amide resin, Fmoc-Ser(O-tBu) for bothFmoc-Thr(O-tBu) and Fmoc-Nva, and adding a coupling with Fmoc-Pro beforethe coupling with Fmoc-Arg(Pmc) in Example 43. After workup the crudepeptide was purified by HPLC using a C-18 column and a solvent systemvarying in gradient over 50 minutes from 5% to 100% acetonitrile/watercontaining 0.01% TFA. The pure fractions were lyophilized to provideN-Ac-Ser-Ser-Ile-Arg-Pro-D-AlaNH₂ as the trifluoracetate salt:R_(t)=3.107 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 671.3 (M+H)⁺.

EXAMPLE 72 N-Ac-Thr-Nva-Pro-Arg-ProNHCH₂CH₃ (SEQ ID NO:23)

The desired product was prepared by substituting Fmoc-Pro for Fmoc-Ilein Example 43. After workup the crude peptide was purified by HPLC usinga C-18 column and a solvent system varying in gradient over 50 minutesfrom 5% to 100% acetonitrile/water containing 0.01% TFA. The purefractions were lyophilized to provide N-Ac-Thr-Nva-Pro-Arg-ProNHCH₂CH₃as the trifluoracetate salt: R_(t)=3.654 minutes (gradient varying over10 minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 638.4 (M+H)⁺.

EXAMPLE 73 N-Ac-Ser-Gln-D-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-Ser(O-tBu) forFmoc-Thr(O-tBu), Fmoc-Gln(Trt) for Fmoc-Nva, and Fmoc-D-Ile for Fmoc-Ilein Example 43. After workup the crude peptide was purified by HPLC usinga C-18 column and a solvent system varying in gradient over 50 minutesfrom 5% to 100% acetonitrile/water containing 0.01% TFA. The purefractions were lyophilized to provide N-Ac-Ser-Gln-D-Ile-Arg-ProNHCH₂CH₃as the trifluoracetate salt: R_(t)=3.382 minutes (gradient varying over10 minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 669.4 (M+H)⁺.

EXAMPLE 74 N-Ac-Thr-Trp-D-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-Trp(Boc) forFmoc-Nva and Fmoc-D-Ile for Fmoc-Ile in Example 43. After workup thecrude peptide was purified by HPLC using a C-18 column and a solventsystem varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-Thr-Trp-D-Ile-Arg-ProNHCH₂CH₃ as thetrifluoracetate salt: R_(t)=5.422 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 741.5 (M+H)⁺.

EXAMPLE 75 N-Ac-Ser-Gln-Lys(Ac)-Arg-ProNHCH₂CH₃ (SEQ ID NO:24)

The desired product was prepared by substituting Fmoc-Ser(O-tBu) forFmoc-Thr(O-tBu), Fmoc-Gln(Trt) for Fmoc-Nva, and Fmoc-Lys(Ac) forFmoc-Ile in Example 43. After workup the crude peptide was purified byHPLC using a C-18 column and a solvent system varying in gradient over50 minutes from 5% to 100% acetonitrile/water containing 0.01% TFA. Thepure fractions were lyophilized to provideN-Ac-Ser-Gln-Lys(Ac)-Arg-ProNHCH₂CH₃ as the trifluoracetate salt:R_(t)=2.710 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 726.4 (M+H)⁺.

EXAMPLE 76 N-Ac-Ser-Gln-Ile-Arg-Pro-D-AlaNH₂

The desired product was prepared by substituting Fmoc-D-Ala-Sieber amideresin for Fmoc-Pro-Sieber ethylamide resin, Fmoc-Ser(O-tBu) forFmoc-Thr(O-tBu), Fmoc-Gln(Trt) for Fmoc-Nva, and adding a coupling withFmoc-Pro before the coupling with Fmoc-Arg(Pmc) in Example 43. Afterworkup the crude peptide was purified by HPLC using a C-18 column and asolvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-Ser-Gln-Ile-Arg-Pro-D-AlaNH₂ as thetrifluoracetate salt: R_(t)=3.004 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 712.4 (M+H)⁺.

EXAMPLE 77 N-Ac-AllylGly-Gln-Ile-Arg-ProNHCH₂CH₃ (SEQ ID NO:25)

The desired product was prepared by substituting Fmoc-AllylGly forFmoc-Thr(O-tBu) and Fmoc-Gln(Trt) for Fmoc-Nva in Example 43. Afterworkup the crude peptide was purified by HPLC using a C-18 column and asolvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-AllylGly-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoracetate salt: R_(t)=4.015 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 679.3 (M+H)⁺.

EXAMPLE 78 N-Ac-Thr-Nva-Lys-Arg-ProNHCH₂CH₃ (SEQ ID NO:26)

The desired product was prepared by substituting Fmoc-Lys(Boc) forFmoc-Ile in Example 43. After workup the crude peptide was purified byHPLC using a C-18 column and a solvent system varying in gradient over50 minutes from 5% to 100% acetonitrile/water containing 0.01% TFA. Thepure fractions were lyophilized to provideN-Ac-Thr-Nva-Lys-Arg-ProNHCH₂CH₃ as the trifluoracetate salt:R_(t)=2.872 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 669.3 (M+H)⁺.

EXAMPLE 79 N-Ac-Ser-D-Gln-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-Ser(O-tBu) forFmoc-Thr(O-tBu) and Fmoc-D-Gln(Trt) for Fmoc-Nva in Example 43. Afterworkup the crude peptide was purified by HPLC using a C-18 column and asolvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-Ser-D-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoracetate salt: R_(t)=3.276 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 669.3 (M+H)⁺.

EXAMPLE 80 N-Ac-D-Ile-Thr-Arg-Ile-Arg-NHCH₂CH₃

The desired product was prepared by substituting Fmoc-Arg(Pmc) forFmoc-Nva and omitting the Fmoc-Pro coupling in Example 1. After workupthe crude peptide was purified by HPLC using a C-18 column and a solventsystem varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-D-Ile-Thr-Arg-Ile-Arg-NHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=1.05 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 727.4 (M+H)⁺; Amino Acid Anal.: 2.01 Ile; 0.56 Thr; 2.31 Arg.

EXAMPLE 81 N-Ac-D-aIle-Ser-Ser-Lys(Ac)-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-aIle forFmoc-D-Ile, Fmoc-Ser(O-tBu) for Fmoc-Thr(O-tBu) and Fmoc-Nva, andFmoc-Lys(Ac) for Fmoc-Ile in Example 1 After workup the crude peptidewas purified by HPLC using a C-18 column and a solvent system varying ingradient over 50 minutes from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions were lyophilized to provideN-Ac-D-aIle-Ser-Ser-Lys(Ac)-Arg-ProNHCH₂CH₃ as the trifluoroacetatesalt: R_(t)=3.671 minutes (gradient varying over 10 minutes from 20% to80% acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 798.7 (M+H)⁺;Amino Acid Anal.: 0.19 Ser; 0.92 Ile; 0.98 Lys; 0.74 Arg; 1.0 Pro.

EXAMPLE 82 N-Ac-D-aIle-Ser-Ser-Nle-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-aIle forFmoc-D-Ile, Fmoc-Ser(O-tBu) for Fmoc-Thr(O-tBu) and Fmoc-Nva, andFmoc-Nle for Fmoc-Ile in Example 1. After workup the crude peptide waspurified by HPLC using a C-18 column and a solvent system varying ingradient over 50 minutes from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions were lyophilized to provideN-Ac-D-aIle-Ser-Ser-Nle-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=4.394 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 741.6 (M+H)⁺;Amino Acid Anal.: 0.34 Ser; 0.99 Ile; 0.96 Nle; 0.99 Arg; 1.05 Pro.

EXAMPLE 83 N-Ac-D-aIle-Ser-Ser-Pro-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-aIle forFmoc-D-Ile, Fmoc-Ser(O-tBu) for Fmoc-Thr(O-tBu) and Fmoc-Nva, andFmoc-Pro for Fmoc-Ile in Example 1. After workup the crude peptide waspurified by HPLC using a C-18 column and a solvent system varying ingradient over 50 minutes from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions were lyophilized to provideN-Ac-D-aIle-Ser-Ser-Pro-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=3.37 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 725.5 (M+H)⁺;Amino Acid Anal.: 0.18 Ser; 1.00 Ile; 0.87 Arg; 2.13 Pro.

EXAMPLE 84 N-Ac-D-aIle-Ser-Ser-Nva-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-aIle forFmoc-D-Ile, Fmoc-Ser(O-tBu) for Fmoc-Thr(O-tBu) and Fmoc-Nva, andFmoc-Nva for Fmoc-Ile in Example 1. After workup the crude peptide waspurified by HPLC using a C-18 column and a solvent system varying ingradient over 50 minutes from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions were lyophilized to provideN-Ac-D-aIle-Ser-Ser-Nva-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=3.938 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 727.5 (M+H)⁺;Amino Acid Anal.: 0.30 Ser; 1.03 Nva; 1.04 Ile; 0.94 Arg; 1.03 Pro.

EXAMPLE 85 N-Ac-D-Ile-Thr-Nva-Ile-Arg-NHCH₂CH₃

The desired product was prepared by omitting the coupling with Fmoc-Proin Example 1. After workup the crude peptide was purified by HPLC usinga C-18 column and a solvent system varying in gradient over 50 minutesfrom 5% to 100% acetonitrile/water containing 0.01% TFA. The purefractions were lyophilized to provideN-Ac-D-Ile-Thr-Nva-Ile-Arg-NHCH₂CH₃ as the trifluoroacetate salt:R_(t)=2.15 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 670.3 (M+H)⁺;Amino Acid Anal.: 0.55 Thr; 1.02 Nva; 2.02 Ile; 1.21 Arg.

EXAMPLE 86 N-Ac-D-aIle-Ser-Ser-Lys-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-aIle forFmoc-D-Ile, Fmoc-Ser(O-tBu) for Fmoc-Thr(O-tBu) and Fmoc-Nva, andFmoc-Lys(Boc) for Fmoc-Ile in Example 1. After workup the crude peptidewas purified by HPLC using a C-18 column and a solvent system varying ingradient over 50 minutes from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions were lyophilized to provideN-Ac-D-aIle-Ser-Ser-Lys-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=3.272 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 756.5 (M+H)⁺.

EXAMPLE 87 N-Ac-D-aIle-Ser-Ser-Ile-Arg-ProNHCH(CH₃)₂

The desired product was prepared by substituting Fmoc-D-aIle forFmoc-D-Ile,Fmoc-Pro-[4-(4-N-isopropylamino)methyl-3-methoxyphenoxy]butyryl AM resinfor Fmoc-Pro Sieber ethylamide resin, and Fmoc-Ser(O-tBu) forFmoc-Thr(O-tBu) and Fmoc-Nva in Example 1. After workup the crudepeptide was purified by HPLC using a C-18 column and a solvent systemvarying in gradient over 50 minutes from 5% to 100% acetonitrile/watercontaining 0.01% TFA. The pure fractions were lyophilized to provideN-Ac-D-aIle-Ser-Ser-Ile-Arg-ProNHCH(CH₃)₂ as the trifluoroacetate salt:R_(t)=3.04 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 755.5 (M+H)⁺.

EXAMPLE 88 N-Ac-D-aIle-Ser-Ser-Gln-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-aIle forFmoc-D-Ile, Fmoc-Ser(O-tBu) for Fmoc-Thr(O-tBu) and Fmoc-Nva, andFmoc-Gln(Trt) for Fmoc-Ile in Example 1. After workup the crude peptidewas purified by HPLC using a C-18 column and a solvent system varying ingradient over 50 minutes from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions were lyophilized to provideN-Ac-D-aIle-Ser-Ser-Gln-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=3.039 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 756.5 (M+H)⁺.

EXAMPLE 89 N-Ac-D-aIle-Ser-Ser-Cit-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-aIle forFmoc-D-Ile, Fmoc-Ser(O-tBu) for Fmoc-Thr(O-tBu) and Fmoc-Nva, andFmoc-Cit for Fmoc-Ile in Example 1. After workup the crude peptide waspurified by HPLC using a C-18 column and a solvent system varying ingradient over 50 minutes from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions were lyophilized to provideN-Ac-D-aIle-Ser-Ser-Cit-Arg-Pro-NHCH₂CH₃ as the trifluoroacetate salt:R_(t)=2.796 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 785.5 (M+H)⁺.

EXAMPLE 90 N-Ac-D-Ile-Met-Gln-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-Met forFmoc-Thr(O-tBu) and Fmoc-Gln(Trt) for Fmoc-Nva in Example 1. Afterworkup the crude peptide was purified by HPLC using a C-18 column and asolvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-D-Ile-Met-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.49 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 826.5 (M+H)⁺.

EXAMPLE 91 N-Ac-Thr-Nva-D-Lys(Ac)-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-Lys(Ac) forFmoc-Ile in Example 43 After workup the crude peptide was purified byHPLC using a C-18 column and a solvent system varying in gradient over50 minutes from 5% to 100% acetonitrile/water containing 0.01% TFA. Thepure fractions were lyophilized to provideN-Ac-Thr-Nva-D-Lys(Ac)-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=0.81 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 711.5 (M+H)⁺.

EXAMPLE 92 N-Ac-Thr-Nva-Ile-Orn-ProNHCH₂CH₃ (SEQ ID NO:27)

The desired product was prepared by substituting Fmoc-Orn(Boc) forFmoc-Arg(Pmc) in Example 43. After workup the crude peptide was purifiedby HPLC using a C-18 column and a solvent system varying in gradientover 50 minutes from 5% to 100% acetonitrile/water containing 0.01% TFA.The pure fractions were lyophilized to provideN-Ac-Thr-Nva-Ile-Orn-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=3.494 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 612.4 (M+H)⁺;Amino Acid Anal.: 0.525 Thr; 1.007 Nva; 1.01 Ile; 1.013 Orn; 0.99 Pro.

EXAMPLE 93 N-Ac-Glu-Nva-Ile-Arg-ProNHCH₂CH₃ (SEQ ID NO:28)

The desired product was prepared by substituting Fmoc-Glu(O-tBu) forFmoc-Thr(O-tBu) in Example 43. After workup the crude peptide waspurified by HPLC using a C-18 column and a solvent system varying ingradient over 50 minutes from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions were lyophilized to provideN-Ac-Glu-Nva-Ile-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=3.676 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/c 682.4 (M+H)⁺;Amino Acid Anal.: 1.014 Glu; 1.003 Nva; 1.007 Ile; 0.964 Arg; 1.015 Pro.

EXAMPLE 94 N-Ac-Asn-Nva-Ile-Arg-ProNHCH₂CH₃ (SEQ ID NO:29)

The desired product was prepared by substituting Fmoc-Asn(Trt) forFmoc-Thr(O-tBu) in Example 43. After workup the crude peptide waspurified by HPLC using a C-18 column and a solvent system varying ingradient over 50 minutes from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions were lyophilized to provideN-Ac-Asn-Nva-Ile-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=3.579 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 667.4 (M+H)⁺;Amino Acid Anal.: 1.018 Asp; 1.052 Nva; 1.047 Ile; 0.998 Arg; 0.938 Pro.

EXAMPLE 95 N-Ac-Hser-Nva-Ile-Arg-ProNHCH₂CH₃ (SEQ ID NO:30)

The desired product was prepared by substituting Fmoc-Hser(Trt) forFmoc-Thr(O-tBu) in Example 43. After workup the crude peptide waspurified by HPLC using a C-18 column and a solvent system varying ingradient over 50 minutes from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions were lyophilized to provideN-Ac-Hser-Nva-Ile-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=1.35 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 654.5 (M+H)⁺;Amino Acid Anal.: 1.35 Hser; 1.052 Nva; 1.002 Ile; 0.972 Arg; 1.026 Pro.

EXAMPLE 96 N-Ac-Sar-Nva-Ile-Arg-ProNHCH₂CH₃ (SEQ ID NO:31)

The desired product was prepared by substituting Fmoc-Sar forFmoc-Thr(O-tBu) in Example 43. After workup the crude peptide waspurified by HPLC using a C-18 column and a solvent system varying ingradient over 50 minutes from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions were lyophilized to provideN-Ac-Sar-Nva-Ile-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=3.60 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 624.4 (M+H)⁺;Amino Acid Anal.: 0.835 Sar; 1.035 Nva; 0.986 Ile; 0.980 Arg; 1.034 Pro.

EXAMPLE 97 N-Ac-Asp-Nva-Ile-Arg-ProNHCH₂CH₃ (SEQ ID NO:32)

The desired product was prepared by substituting Fmoc-Asp(O-tBu) forFmoc-Thr(O-tBu) in Example 43. After workup the crude peptide waspurified by HPLC using a C-18 column and a solvent system varying ingradient over 50 minutes from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions were lyophilized to provideN-Ac-Asp-Nva-Ile-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=3.622 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 668.4 (M+H)⁺;Amino Acid Anal.: 1.036 Asp; 1.054 Nva; 1.045 Ile; 0.982 Arg; 0.937 Pro.

EXAMPLE 98 N-Ac-Ser-Gln-Nva-Arg-ProNHCH₂CH₃ (SEQ ID NO:33)

The desired product was prepared by substituting Fmoc-Ser(O-tBu) forFmoc-Thr(O-tBu), Fmoc-Gln(Trt) for Fmoc-Nva, and Fmoc-Nva for Fmoc-Ilein Example 43. After workup the crude peptide was purified by HPLC usinga C-18 column and a solvent system varying in gradient over 50 minutesfrom 5% to 100% acetonitrile/water containing 0.01% TFA. The purefractions were lyophilized to provide N-Ac-Ser-Gln-Nva-Arg-ProNHCH₂CH₃as the trifluoroacetate salt: R_(t)=3.253 minutes (gradient varying over10 minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 655.4 (M+H)⁺; Amino Acid Anal.: 0.224 Ser; 1.046 Glu; 0.845Nva; 0.969 Arg; 0.985 Pro.

EXAMPLE 99 N-Ac-Ser-Gln-Ile-Cit-ProNHCH₂CH₃ (SEQ ID NO:34)

The desired product was prepared by substituting Fmoc-Ser(O-tBu) forFmoc-Thr(O-tBu), Fmoc-Gln(Trt) for Fmoc-Nva, and Fmoc-Cit forFmoc-Arg(Pmc) in Example 43. After workup the crude peptide was purifiedby HPLC using a C-18 column and a solvent system varying in gradientover 50 minutes from 5% to 100% acetonitrile/water containing 0.01% TFA.The pure fractions were lyophilized to provideN-Ac-Ser-Gln-Ile-Cit-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=3.253 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 655.4 (M+H)⁺;Amino Acid Anal.: 0.273 Ser; 1.012 Glu; 0.939 Ile; 1.043 Cit; 1.04 Pro.

EXAMPLE 100 N-Ac-Ser-Gln-Ile-3Pal-ProNHCH₂CH₃ (SEQ ID NO:35)

The desired product was prepared by substituting Fmoc-Ser(O-tBu) forFmoc-Thr(O-tBu), Fmoc-Gln(Trt) for Fmoc-Nva, and Fmoc-3Pal forFmoc-Arg(Pmc) in Example 43. After workup the crude peptide was purifiedby HPLC using a C-18 column and a solvent system varying in gradientover 50 minutes from 5% to 100% acetonitrile/water containing 0.01% TFA.The pure fractions were lyophilized to provideN-Ac-Ser-Gln-Ile-3Pal-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=4.031 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 661.3 (M+H)⁺;Amino Acid Anal.: 0.23 Ser; 1.012 Glu; 1.025 Ile; 0.793 3Pal; 0.963 Pro.

EXAMPLE 101 N-Ac-Thr-Gln-Nva-Arg-ProNHCH₂CH₃ (SEQ ID NO:36)

The desired product was prepared by substituting Fmoc-Gln(Trt) forFmoc-Nva and Fmoc-Nva for Fmoc-Ile in Example 43. After workup the crudepeptide was purified by HPLC using a C-18 column and a solvent systemvarying in gradient over 50 minutes from 5% to 100% acetonitrile/watercontaining 0.01% TFA. The pure fractions were lyophilized to provideN-Ac-Thr-Gln-Nva-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt: R_(t)=3.4minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 669.4 (M+H)⁺;Amino Acid Anal.: 0.535 Thr; 1.023 Glu; 1.09 Nva; 1.013 Arg; 0.964 Pro.

EXAMPLE 102 N-Ac-Thr-Asn-Ile-Arg-ProNHCH₂CH₃ (SEQ ID NO:37)

The desired product was prepared by substituting Fmoc-Asn(Trt) forFmoc-Nva in Example 43. After workup the crude peptide was purified byHPLC using a C-18 column and a solvent system varying in gradient over50 minutes from 5% to 100% acetonitrile/water containing 0.01% TFA. Thepure fractions were lyophilized to provideN-Ac-Thr-Asn-Ile-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt: R_(t)=3.4minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 669.4 (M+H)⁺;Amino Acid Anal.: 0.591 Thr; 1.02 Asp; 1.003 Ile; 1.005 Arg; 0.972 Pro.

EXAMPLE 103 N-Ac-Thr-D-Asn-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-Asn(Trt) forFmoc-Nva in Example 43. After workup the crude peptide was purified byHPLC using a C-18 column and a solvent system varying in gradient over50 minutes from 5% to 100% acetonitrile/water containing 0.01% TFA. Thepure fractions were lyophilized to provideN-Ac-Thr-D-Asn-Ile-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=3.615 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 669.4 (M+H)⁺;Amino Acid Anal.: 0.62 Thr; 0.908 Asp; 0.995 Ile; 1.044 Arg; 1.053 Pro.

EXAMPLE 104 H-Thr-Nva-Pro-Arg-ProNHCH₂CH₃ (SEQ ID NO:38)

The desired product was prepared by substituting Fmoc-Pro for Fmoc-Ileand omitting the last acetylation step in Example 43. After workup thecrude peptide was purified by HPLC using a C-18 column and a solventsystem varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide H-Thr-Nva-Pro-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.30 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 596.4 (M+H)⁺; Amino Acid Anal.: 0.604 Thr; 1.20 Nva; 0.955Arg; 2.045 Pro.

EXAMPLE 105 N-Ac-D-Thr-Nva-Pro-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-Thr(O-tBu) forFmoc-Thr(O-tBu) and Fmoc-Pro for Fmoc-Ile in Example 43. After workupthe crude peptide was purified by HPLC using a C-18 column and a solventsystem varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-D-Thr-Nva-Pro-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.82 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 638.5 (M+H)⁺; Amino Acid Anal.: 0.568 Thr; 1.17 Nva; 0.997Arg; 2.003 Pro.

EXAMPLE 106 N-Ac-Thr-Nva-D-Pro-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-Pro for Fmoc-Ilein Example 43. After workup the crude peptide was purified by HPLC usinga C-18 column and a solvent system varying in gradient over 50 minutesfrom 5% to 100% acetonitrile/water containing 0.01% TFA. The purefractions were lyophilized to provide N-Ac-Thr-Nva-D-Pro-Arg-ProNHCH₂CH₃as the trifluoroacetate salt: R_(t)=3.45 minutes (gradient varying over10 minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 638.4 (M+H)⁺; Amino Acid Anal.: 0.614 Thr; 1.195 Nva; 1.073Arg; 1.927 Pro.

EXAMPLE 107 N-Ac-Nva-Gln-Ile-Arg-ProNHCH₂CH₃ (SEQ ID NO:39)

The desired product was prepared by substituting Fmoc-Nva forFmoc-Thr(O-tBu) and Fmoc-Gln(Trt) for Fmoc-Nva in Example 43. Afterworkup the crude peptide was purified by HPLC using a C-18 column and asolvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-Nva-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.822 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 681.5.

EXAMPLE 108 N-Ac-D-Nva-Pro-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-Nva forFmoc-Thr(O-tBu) and Fmoc-Pro for Fmoc-Nva in Example 43. After workupthe crude peptide was purified by HPLC using a C-18 column and a solventsystem varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-D-Nva-Pro-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=5.008 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 638.4.

EXAMPLE 109 N-Ac-Thr-Arg-Ile-Cit-ProNHCH₂CH₃ (SEQ ID NO:40)

The desired product was prepared by substituting Fmoc-Arg(Pmc) forFmoc-Nva and Fmoc-Cit for Fmoc-Arg(Pmc) in Example 43. After workup thecrude peptide was purified by HPLC using a C-18 column and a solventsystem varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-Thr-Arg-Ile-Cit-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.868 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 712.5.

EXAMPLE 110 N-Ac-Thr-Gln-Lys(Ac)-Arg-ProNHCH₂CH₃ (SEQ ID NO:41)

The desired product was prepared by substituting Fmoc-Gln(Trt) forFmoc-Nva and Fmoc-Lys(Ac) for Fmoc-Ile in Example 43. After workup thecrude peptide was purified by HPLC using a C-18 column and a solventsystem varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-Thr-Gln-Lys(Ac)-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.334 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 740.5.

EXAMPLE 111 N-Ac-Thr-Nva-Pro-Arg-Pro-D-AlaNH₂

The desired product was prepared by substituting Fmoc-D-Ala-Sieber amideresin for Fmoc-Pro-Sieber ethylamide resin, adding a coupling withFmoc-Pro before the coupling with Fmoc-Arg(Pmc), and substitutingFmoc-Pro for Fmoc-Ile in Example 43. After workup the crude peptide waspurified by HPLC using a C-18 column and a solvent system varying ingradient over 50 minutes from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions were lyophilized to provideN-Ac-Thr-Nva-Pro-Arg-Pro-D-AlaNH₂ as the trifluoroacetate salt:R_(t)=2.943 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 681.5.

EXAMPLE 112 N-Ac-Thr-Ser-Lys(Ac)-Arg-ProNHCH₂CH₃ (SEQ ID NO:42)

The desired product was prepared by substituting Fmoc-Ser(O-tBu) forFmoc-Nva and Fmoc-Lys(Ac) for Fmoc-Ile in Example 43. After workup thecrude peptide was purified by HPLC using a C-18 column and a solventsystem varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-Thr-Ser-Lys(Ac)-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.428 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 699.5.

EXAMPLE 113 N-Ac-Thr-Ser-Pro-Arg-Pro-D-AlaNH₂

The desired product was prepared by substituting Fmoc-D-Ala-Sieber amideresin for Fmoc-Pro-Sieber ethylamide resin, adding a coupling withFmoc-Pro before the coupling with Fmoc-Arg(Pmc), and substitutingFmoc-Ser(O-tBu) for Fmoc-Nva and Fmoc-Pro for Fmoc-Ile in Example 43.After workup the crude peptide was purified by HPLC using a C-18 columnand a solvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-Thr-Ser-Pro-Arg-Pro-D-AlaNH₂ as thetrifluoroacetate salt: R_(t)=2.028 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 669.3.

EXAMPLE 114 N-Ac-Thr-Cit-Ile-Arg-ProNHCH₂CH₃ (SEQ ID NO:43)

The desired product was prepared by substituting Fmoc-Cit for Fmoc-Nvain Example 43. After workup the crude peptide was purified by HPLC usinga C-18 column and a solvent system varying in gradient over 50 minutesfrom 5% to 100% acetonitrile/water containing 0.01% TFA. The purefractions were lyophilized to provide N-Ac-Thr-Cit-Ile-Arg-ProNHCH₂CH₃as the trifluoroacetate salt: R_(t)=2.839 minutes (gradient varying over10 minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 712.5.

EXAMPLE 115 N-(3-Methylvaleryl)-Thr-Gln-Ile-Arg-ProNHCH₂CH₃ (SEQ IDNO:44)

The desired product was prepared by substituting Fmoc-Gln(Trt) forFmoc-Nva and 3-methylvaleric acid for acetic acid in Example 43. Afterworkup the crude peptide was purified by HPLC using a C-18 column and asolvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-(3-methylvaleryl)-Thr-Gln-Ile-Arg-ProNHCH₂CH₃as the trifluoroacetate salt: R_(t)=4.501 minutes (gradient varying over10 minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 739.5.

EXAMPLE 116 N-(3-Methylvaleryl)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ (SEQ IDNO:45)

The desired product was prepared by substituting 3-methylvaleric acidfor acetic acid in Example 43. After workup the crude peptide waspurified by HPLC using a C-18 column and a solvent system varying ingradient over 50 minutes from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions were lyophilized to provideN-(3-methylvaleryl)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as the trifluoroacetatesalt: R_(t)=4.82 minutes (gradient varying over 10 minutes from 20% to80% acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 710.5.

EXAMPLE 117 N-Ac-Ser-Trp-Ile-Arg-ProNHCH₂CH₃ (SEQ ID NO:46)

The desired product was prepared by substituting Fmoc-Ser(O-tBu) forFmoc-Thr(O-tBu) and Fmoc-Trp(Boc) for Fmoc-Nva in Example 43. Afterworkup the crude peptide was purified by HPLC using a C-18 column and asolvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-Ser-Trp-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.539 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 727.4.

EXAMPLE 118 N-Ac-Thr-Trp-Ile-Arg-ProNHCH₂CH₃ (SEQ ID NO:47)

The desired product was prepared by substituting Fmoc-Trp(Boc) forFmoc-Nva in Example 43. After workup the crude peptide was purified byHPLC using a C-18 column and a solvent system varying in gradient over50 minutes from 5% to 100% acetonitrile/water containing 0.01% TFA. Thepure fractions were lyophilized to provideN-Ac-Thr-Trp-Ile-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=4.589 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 741.5.

EXAMPLE 119 N-Ac-D-Nva-Gln-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-Nva forFmoc-Thr(O-tBu) and Fmoc-Gln(Trt) for Fmoc-Nva in Example 43. Afterworkup the crude peptide was purified by HPLC using a C-18 column and asolvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-D-Nva-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.692 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 681.4.

EXAMPLE 120 N-Ac-Thr-Lys(Ac)-Ile-Arg-ProNHCH₂CH₃ (SEQ ID NO:48)

The desired product was prepared by substituting Fmoc-Lys(Ac) forFmoc-Nva in Example 43. After workup the crude peptide was purified byHPLC using a C-18 column and a solvent system varying in gradient over50 minutes from 5% to 100% acetonitrile/water containing 0.01% TFA. Thepure fractions were lyophilized to provideN-Ac-Thr-Lys(Ac)-Ile-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=3.311 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 725.5.

EXAMPLE 121 N-Ac-bAla-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ (SEQ ID NO:49)

The desired product was prepared by coupling with Fmoc-β-alanine beforethe coupling with acetic acid in Example 43. After workup the crudepeptide was purified by HPLC using a C-18 column and a solvent systemvarying in gradient over 50 minutes from 5% to 100% acetonitrile/watercontaining 0.01% TFA. The pure fractions were lyophilized to provideN-Ac-bAla-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=3.625 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 725.5.

EXAMPLE 122 N-Ac-bAla-Thr-Gln-Ile-Arg-ProNHCH₂CH₃ (SEQ ID NO:50)

The desired product was prepared by substituting Fmoc-Gln(Trt) forFmoc-Nva and coupling with Fmoc-β-alanine before the coupling withacetic acid in Example 43. After workup the crude peptide was purifiedby HPLC using a C-18 column and a solvent system varying in gradientover 50 minutes from 5% to 100% acetonitrile/water containing 0.01% TFA.The pure fractions were lyophilized to provideN-Ac-bAla-Thr-Gln-Ile-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt:R_(t)=2.844 minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 754.5.

EXAMPLE 123 N-Ac-Ser-D-Gln-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-Ser(O-tBu) forFmoc-Thr(O-tBu) and Fmoc-D-Gln(Trt) for Fmoc-Nva in Example 43. Afterworkup the crude peptide was purified by HPLC using a C-18 column and asolvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-Ser-D-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.542 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 712.4.

EXAMPLE 124 N-Ac-D-Leu-Asp-Nva-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-Leu forFmoc-D-Ile and Fmoc-Asp(O-tBu) for Fmoc-Thr(O-tBu) in Example 1. Afterworkup the crude peptide was purified by HPLC using a C-18 column and asolvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-D-Leu-Asp-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=1.86 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 781.6; Amino Acid Anal.: 1.01 Leu; 0.97 Asp; 1.00 Nva; 1.03Ile; 1.10 Arg; 1.06 Pro.

EXAMPLE 125 N-Ac-D-Ile-Gln-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-Ile forFmoc-Thr(O-tBu) and Fmoc-Gln(Trt) for Fmoc-Nva in Example 43. Afterworkup the crude peptide was purified by HPLC using a C-18 column and asolvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-D-Ile-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.73 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 695.4.

EXAMPLE 126 N-Ac-D-Ala-Gln-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-Ala forFmoc-Thr(O-tBu) and Fmoc-Gln(Trt) for Fmoc-Nva in Example 43. Afterworkup the crude peptide was purified by HPLC using a C-18 column and asolvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-D-Ala-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.981 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 653.4.

EXAMPLE 127 N-Ac-D-Thr-Gln-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-Thr(O-tBu) forFmoc-Thr(O-tBu) and Fmoc-Gln(Trt) for Fmoc-Nva in Example 43. Afterworkup the crude peptide was purified by HPLC using a C-18 column and asolvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-D-Thr-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.927 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 683.4.

EXAMPLE 128 N-Ac-D-Ser-Gln-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-Ser(O-tBu) forFmoc-Thr(O-tBu) and Fmoc-Gln(Trt) for Fmoc-Nva in Example 43. Afterworkup the crude peptide was purified by HPLC using a C-18 column and asolvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-D-Ser-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.763 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 669.3.

EXAMPLE 129 N-Ac-D-Pro-Gin-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-Pro forFmoc-Thr(O-tBu) and Fmoc-Gln(Trt) for Fmoc-Nva in Example 43. Afterworkup the crude peptide was purified by HPLC using a C-18 column and asolvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-D-Pro-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.376 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 679.4.

EXAMPLE 130 N-Ac-D-aIle-Gln-Ile-Arg-ProNHCH₂CH₃

The desired product was prepared by substituting Fmoc-D-aIle forFmoc-Thr(O-tBu) and Fmoc-Gln(Trt) for Fmoc-Nva in Example 43. Afterworkup the crude peptide was purified by HPLC using a C-18 column and asolvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-D-aIle-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.778 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 695.4.

EXAMPLE 131 N-Ac-D-Nva-Asn-Ile-Arg-ProNHCH₂CH₃

The desired product can be prepared by substituting Fmoc-D-Nva forFmoc-Thr(O-tBu) and Fmoc-Asn(Trt) for Fmoc-Nva in Example 43. Afterworkup the crude peptide can be purified by HPLC using a C-18 column anda solvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions can belyophilized to provide N-Ac-D-Nva-Asn-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 132 N-Ac-D-Nva-Arg-Ile-Arg-ProNHCH₂CH₃

The desired product can be prepared by substituting Fmoc-D-Nva forFmoc-Thr(O-tBu) and Fmoc-Arg(Pmc) for Fmoc-Nva in Example 43. Afterworkup the crude peptide can be purified by HPLC using a C-18 column anda solvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions can belyophilized to provide N-Ac-D-Nva-Arg-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 133 N-Ac-D-Nva-Thr-Ile-Arg-ProNHCH CH₃

The desired product can be prepared by substituting Fmoc-D-Nva forFmoc-Thr(O-tBu) and Fmoc-Thr(O-tBu) for Fmoc-Nva in Example 43. Afterworkup the crude peptide can be purified by HPLC using a C-18 column anda solvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions can belyophilized to provide N-Ac-D-Nva-Thr-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 134 N-Ac-D-Nva-Ser-Ile-Arg-ProNHCH₂CH₃

The desired product can be prepared by substituting Fmoc-D-Nva forFmoc-Thr(O-tBu) and Fmoc-Ser(O-tBu) for Fmoc-Nva in Example 43. Afterworkup the crude peptide can be purified by HPLC using a C-18 column anda solvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions can belyophilized to provide N-Ac-D-Nva-Ser-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 135 N-Ac-D-Nva-Glu-Ile-Arg-ProNHCH₂CH₃

The desired product can be prepared by substituting Fmoc-D-Nva forFmoc-Thr(O-tBu) and Fmoc-Glu(O-tBu) for Fmoc-Nva in Example 43. Afterworkup the crude peptide can be purified by HPLC using a C-18 column anda solvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions can belyophilized to provide N-Ac-D-Nva-Glu-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 136 N-Ac-D-Met-Gln-Ile-Arg-ProNHCH₂CH₃

The desired product can be prepared by substituting Fmoc-D-Met forFmoc-Thr(O-tBu) and Fmoc-Gln(Trt) for Fmoc-Nva in Example 43. Afterworkup the crude peptide can be purified by HPLC using a C-18 column anda solvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions can belyophilized to provide N-Ac-D-Met-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 137 N-Ac-D-Hser-Gln-Ile-Arg-ProNHCH₂CH₃

The desired product can be prepared by substituting Fmoc-D-Hser(Trt) forFmoc-Thr(O-tBu) and Fmoc-Gln(Trt) for Fmoc-Nva in Example 43. Afterworkup the crude peptide can be purified by HPLC using a C-18 column anda solvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions can belyophilized to provide N-Ac-D-Hser-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 138 N-Ac-D-Nva-Lys(Nic)-Ile-Arg-ProNHCH₂CH₃

The desired product can be prepared by substituting Fmoc-D-Nva forFmoc-Thr(O-tBu) and Fmoc-Lys(Nic) for Fmoc-Nva in Example 43. Afterworkup the crude peptide can be purified by HPLC using a C-18 column anda solvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions can belyophilized to provide N-Ac-D-Nva-Lys(Nic)-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 139 N-Ac-D-Nva-Gln-Lys(Ac)-Arg-ProNHCH₂CH₃

The desired product can be prepared by substituting Fmoc-D-Nva forFmoc-Thr(O-tBu), Fmoc-Gln(Trt) for Fmoc-Nva, and Fmoc-Lys(Ac) forFmoc-Ile in Example 43. After workup the crude peptide can be purifiedby HPLC using a C-18 column and a solvent system varying in gradientover 50 minutes from 5% to 100% acetonitrile/water containing 0.01% TFA.The pure fractions can be lyophilized to provideN-Ac-D-Nva-Gln-Lys(Ac)-Arg-ProNHE as the trifluoroacetate salt.

EXAMPLE 140 N-Ac-D-Nva-Gln-Ile-Arg-Pro-D-AlaNH₂

The desired product can be prepared by substituting Fmoc-D-Ala-Sieberamide resin for Fmoc-Pro-Sieber ethylamide resin, adding a coupling withFmoc-Pro before the coupling with Fmoc-Arg(Pmc), and substitutingFmoc-D-Nva for Fmoc-Thr(O-tBu) and Fmoc-Gln(Trt) for Fmoc-Nva in Example43. After workup the crude peptide can be purified by HPLC using a C-18column and a solvent system varying in gradient over 50 minutes from 5%to 100% acetonitrile/water containing 0.01% TFA. The pure fractions canbe lyophilized to provide N-Ac-D-Nva-Gln-Ile-Arg-Pro-D-AlaNH₂ as thetrifluoroacetate salt.

EXAMPLE 141 N-Ac-D-Nva-Gln-Ile-Cit-ProNHCH₂CH₃

The desired product can be prepared by substituting Fmoc-D-Nva forFmoc-Thr(O-tBu), Fmoc-Gln(Trt) for Fmoc-Nva, and Fmoc-Cit forFmoc-Arg(Pmc) in Example 43. After workup the crude peptide can bepurified by HPLC using a C-18 column and a solvent system varying ingradient over 50 minutes from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions can be lyophilized to provideN-Ac-D-Nva-Gln-Ile-Cit-ProNHCH₂CH₃ as the trifluoroacetate salt.

EXAMPLE 142 N-Ac-D-Nva-Gln-Pro-Arg-ProNHCH₂CH₃

The desired product can be prepared by substituting Fmoc-D-Nva forFmoc-Thr(O-tBu), Fmoc-Gln(Trt) for Fmoc-Nva, and Fmoc-Pro for Fmoc-Ilein Example 43. After workup the crude peptide can be purified by HPLCusing a C-18 column and a solvent system varying in gradient over 50minutes from 5% to 100% acetonitrile/water containing 0.01% TFA. Thepure fractions can be lyophilized to provideN-Ac-D-Nva-Gln-Pro-Arg-ProNHE as the trifluoroacetate salt.

EXAMPLE 143 N-Ac-D-Nva-Gln-Ile-Lys(Isp)-ProNHCH₂CH₃

The desired product can be prepared by substituting Fmoc-D-Nva forFmoc-Thr(O-tBu), Fmoc-Gln(Trt) for Fmoc-Nva, and Fmoc-Lys(Isp) forFmoc-Arg(Pmc) in Example 43. After workup the crude peptide can bepurified by HPLC using a C-18 column and a solvent system varying ingradient over 50 minutes from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions can be lyophilized to provideN-Ac-D-Nva-Gln-Ile-Lys(Isp)-ProNHCH₂CH₃ as the trifluoroacetate salt.

EXAMPLE 144 N-Ac-D-Nle-Gln-Ile-Arg-ProNHCH₂CH₃

The desired product can be prepared by substituting Fmoc-D-Nle forFmoc-Thr(O-tBu) and Fmoc-Gln(Trt) for Fmoc-Nva in Example 43. Afterworkup the crude peptide can be purified by HPLC using a C-18 column anda solvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions can belyophilized to provide N-Ac-D-Nle-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 145 N-Ac-Nle-Gln-Ile-Arg-ProNHCH₂CH₃ (SEQ ID NO:51)

The desired product can be prepared by substituting Fmoc-Nle forFmoc-Thr(O-tBu) and Fmoc-Gln(Trt) for Fmoc-Nva in Example 43. Afterworkup the crude peptide can be purified by HPLC using a C-18 column anda solvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions can belyophilized to provide N-Ac-Nle-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 146 N-Ac-D-Nva-Gln-Ile-Arg-ProNHCH(CH₃)₂

The desired product can be prepared by substituting Fmoc-D-Nva forFmoc-Thr(O-tBu), Fmoc-Gln(Trt) for Fmoc-Nva, andFmoc-Pro-[4-(4-N-isopropylamino)methyl-3-methoxyphenoxy]butyryl AM resinfor Fmoc-Pro Sieber ethylamide resin in Example 43. After workup thecrude peptide can be purified by HPLC using a C-18 column and a solventsystem varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions can belyophilized to provide N-Ac-D-Nva-Gln-Ile-Arg-ProNHIsp as thetrifluoroacetate salt.

EXAMPLE 147 N-(6MeNic)-D-Nva-Gln-Ile-Arg-ProNHCH₂CH₃

The desired product can be prepared by substituting Fmoc-D-Nva forFmoc-Thr(O-tBu), Fmoc-Gln(Trt) for Fmoc-Nva, and 6-methylnicotinic acidfor acetic acid in Example 43. After workup the crude peptide can bepurified by HPLC using a C-18 column and a solvent system varying ingradient over 50 minutes from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions can be lyophilized to provideN-(6MeNic)-D-Nva-Gln-Ile-Arg-ProNHCH₂CH₃ as the trifluoroacetate salt.

EXAMPLE 148 N-Ac-Nva-D-Gln-Ile-Arg-ProNHCH₂CH₃

The desired product can be prepared by substituting Fmoc-Nva forFmoc-Thr(O-tBu) and Fmoc-D-Gln(Trt) for Fmoc-Nva in Example 43. Afterworkup the crude peptide can be purified by HPLC using a C-18 column anda solvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions can belyophilized to provide N-Ac-Nva-D-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 149 N-Ac-Nva-D-Asn-Ile-Arg-ProNHCH₂CH₃

The desired product can be prepared by substituting Fmoc-Nva forFmoc-Thr(O-tBu) and Fmoc-D-Asn(Trt) for Fmoc-Nva in Example 43. Afterworkup the crude peptide can be purified by HPLC using a C-18 column anda solvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions can belyophilized to provide N-Ac-Nva-D-Asn-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 150 N-Ac-Nva-D-Ser-Ile-Arg-ProNHCH₂CH₃

The desired product can be prepared by substituting Fmoc-Nva forFmoc-Thr(O-tBu) and Fmoc-D-Ser(O-tBu) for Fmoc-Nva in Example 43. Afterworkup the crude peptide can be purified by HPLC using a C-18 column anda solvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions can belyophilized to provide N-Ac-Nva-D-Ser-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 151 N-Ac-Nva-D-Leu-Ile-Arg-ProNHCH₂CH₃

The desired product can be prepared by substituting Fmoc-Nva forFmoc-Thr(O-tBu) and Fmoc-D-Leu for Fmoc-Nva in Example 43. After workupthe crude peptide can be purified by HPLC using a C-18 column and asolvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions can belyophilized to provide N-Ac-Nva-D-Leu-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 152 N-Ac-Sar-Gly-Val-D-a le-Thr-OH

In the reaction vessel of a Rainin peptide synthesizer was placedH-Thr(O-tBu)-2-Chlorotrityl resin (0.2 g, 0.52 mMol/g loading). Theresin was solvated with DMF and amino acids were coupled sequentiallyaccording to the following synthetic cycle:

-   (1) 3×1.5 minute washes with DMF;-   (2) 2×15 minute deprotections using 20% piperidine;-   (3) 6×3 minute washes with DMF;-   (4) addition of amino acid;-   (5) activation of amino acid with 0.4 M HBTU/NMM and coupling;-   (6) 3×1.5 minute washes with DMF.

The protected amino acids were coupled to the resin in the followingorder:

Protected Amino Acid Coupling time Fmoc-D-aIle 30 minutes Fmoc-Val 30minutes Fmoc-Gly 30 minutes Fmoc-Sar 30 minutes Acetic acid 30 minutes

Upon completion of the synthesis the peptide was cleaved from the resinusing a mixture of (95:2.5:2.5) TFA/anisole/water for 3 hours. Thepeptide solution was concentrated under vacuum and then precipitatedwith diethyl ether and collected by filtration. The crude peptide waspurified by HPLC using a C-18 column and a solvent mixture varying over50 minutes in a gradient from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions were lyophilized to provideN-Ac-Sar-Gly-Val-D-aIle-Thr-OH: R_(t)=0.60 minutes (gradient varyingover 10 minutes from 20% to 80% acetonitrile/water containing 0.01%TFA); MS (ESI) m/e 502.28.

EXAMPLE 153 N-Ac-Thr-Gln-Ile-Arg-NHCH₂CH₃ (SEQ ID NO:52)

The desired product was prepared by substitutingFmoc-Arg(Pbf)-[4-(4-N-ethyl)methyl-3-methoxyphenoxy]butyryl AM resinethylamide resin for Fmoc-Pro Sieber ethylamide resin, Fmoc-Gln(Trt) forFmoc-Nva, and omitting the coupling with-Fmoc-Arg(Pmc) in Example 43.After workup the crude peptide was purified by HPLC using a C-18 columnand a solvent system varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to provide N-Ac-Thr-Gln-Ile-Arg-NHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.771 minutes (gradient varying over 10minutes from 20% to 80% acetonitrile/water containing 0.01% TFA); MS(ESI) m/e 586.3.

EXAMPLE 154 N-Ac-Thr-Nva-Ile-Arg-NHCH₂CH₃ (SEQ ID NO:53)

The desired product was prepared by substitutingFmoc-Arg(Pbf)-[4-(4-N-ethyl)methyl-3-methoxyphenoxy]butyryl AM resinethylamide resin for Fmoc-Pro Sieber ethylamide resin and omitting thecoupling with Fmoc-Arg(Pmc) in Example 43. After workup the crudepeptide was purified by HPLC using a C-18 column and a solvent systemvarying in gradient over 50 minutes from 5% to 100% acetonitrile/watercontaining 0.01% TFA. The pure fractions were lyophilized to provideN-Ac-Thr-Nva-Ile-Arg-NHCH₂CH₃ as the trifluoroacetate salt: R_(t)=3.586minutes (gradient varying over 10 minutes from 20% to 80%acetonitrile/water containing 0.01% TFA); MS (ESI) m/e 557.3.

EXAMPLE 155 N-Ac-D-Ile-Thr-Gln-Ile-Arg-NHCH₂CH₃

The desired product can be prepared by substitutingFmoc-Arg(Pbf)-[4-(4-N-ethyl)methyl-3-methoxyphenoxy]butyryl AM resinethylamide resin for Fmoc-Pro Sieber ethylamide resin, Fmoc-Gln(Trt) forFmoc-Nva, and omitting the coupling with Fmoc-Arg(Pmc) in Example 1.After workup the crude peptide can be purified by HPLC using a C-18column and a solvent system varying in gradient over 50 minutes from 5%to 100% acetonitrile/water containing 0.01% TFA. The pure fractions canbe lyophilized to provide N-Ac-D-Ile-Thr-Gln-Ile-Arg-NHCH₂CH₃ as thetrifluoroacetate salt

EXAMPLE 156 N-Ac-D-Ile-Thr-Nva-Lys(Ac)-Arg-NHCH₂CH₃

The desired product can be prepared by substitutingFmoc-Arg(Pbf)-[4-(4-N-ethyl)methyl-3-methoxyphenoxy]butyryl AM resinethylamide resin for Fmoc-Pro Sieber ethylamide resin, Fmoc-Lys(Ac) forFmoc-Ile, and omitting the coupling with Fmoc-Arg(Pmc) in Example 1.After workup the crude peptide can be purified by HPLC using a C-18column and a solvent system varying in gradient over 50 minutes from 5%to 100% acetonitrile/water containing 0.01% TFA. The pure fractions canbe lyophilized to provide N-Ac-D-IleThr-Nva-Lys(Ac)-Arg-NHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 157 N-Ac-D-Ile-Ser-Gln-Ile-Arg-NHCH₂CH₃

The desired product can be prepared by substitutingFmoc-Arg(Pbf)-[4-(4-N-ethyl)methyl-3-methoxyphenoxy]butyryl AM resinethylamide resin for Fmoc-Pro Sieber ethylamide resin, Fmoc-Ser(O-tBu)for Fmoc-Thr(O-tBu), Fmoc-Gln(Trt) for Fmoc-Nva, and omitting thecoupling with Fmoc-Arg(Pmc) in Example 1. After workup the crude peptidecan be purified by HPLC using a C-18 column and a solvent system varyingin gradient over 50 minutes from 5% to 100% acetonitrile/watercontaining 0.01% TFA. The pure fractions can be lyophilized to provideN-Ac-D-Ile-Ser-Gln-Ile-Arg-NHCH₂CH₃ as the trifluoroacetate salt.

EXAMPLE 158 N-Ac-D-aIle-Ser-Ser-Ile-Arg-NHCH₂CH₃

The desired product can be prepared by substitutingFmoc-Arg(Pbf)-[4-(4-N-ethyl)methyl-3-methoxyphenoxy]butyryl AM resinethylamide resin for Fmoc-Pro Sieber ethylamide resin, Fmoc-D-aIle forFmoc-D-Ile, Fmoc-Ser(O-tBu) for Fmoc-Thr(O-tBu) and Fmoc-Nva, andomitting the coupling with Fmoc-Arg(Pmc) in Example 1. After workup thecrude peptide can be purified by HPLC using a C-18 column and a solventsystem varying in gradient over 50 minutes from 5% to 100%acetonitrile/water containing 0.01% TFA. The pure fractions can belyophilized to provide N-Ac-D-aIle-Ser-Ser-Ile-Arg-NHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 159 N-Ac-D-aIle-Thr-Nva-Ile-Arg-NHCH₂CH₃

The desired product can be prepared by substitutingFmoc-Arg(Pbf)-[4-(4-N-ethyl)methyl-3-methoxyphenoxy]butyryl AM resinethylamide resin for Fmoc-Pro Sieber ethylamide resin, Fmoc-D-aIle forFmoc-D-Ile, and omitting the coupling with Fmoc-Arg(Pmc) in Example 1.After workup the crude peptide can be purified by HPLC using a C-18column and a solvent system varying in gradient over 50 minutes from 5%to 100% acetonitrile/water containing 0.01% TFA. The pure fractions canbe lyophilized to provide N-Ac-D-aIle-Thr-Nva-Ile-Arg-NHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 160 N-Ac-D-Ile-Thr-Gln-Lys(Ac)-Arg-NHCH₂CH₃

The desired product can be prepared by substitutingFmoc-Arg(Pbf)-[4-(4-N-ethyl)methyl-3-methoxyphenoxy]butyryl AM resinethylamide resin for Fmoc-Pro Sieber ethylamide resin, Fmoc-Gln(Trt) forFmoc-Nva, Fmoc-Lys(Ac) for Fmoc-Ile, and omitting the coupling withFmoc-Arg(Pmc) in Example 1. After workup the crude peptide can bepurified by HPLC using a C-18 column and a solvent system varying ingradient over 50 minutes from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions can be lyophilized to provideN-Ac-D-Ile-Thr-Gln-Lys(Ac)-Arg-NHCH₂CH₃ as the trifluoroacetate salt.

EXAMPLE 161 N-Ac-D-aIle-Ser-Nva-Lys(Ac)-Arg-NHCH₂CH₃

The desired product can be prepared by substitutingFmoc-Arg(Pbf)-[4-(4-N-ethyl)methyl-3-methoxyphenoxy]butyryl AM resinethylamide resin for Fmoc-Pro Sieber ethylamide resin, Fmoc-D-aIle forFmoc-D-Ile, Fmoc-Ser(O-tBu) for Fmoc-Thr(O-tBu), Fmoc-Lys(Ac) forFmoc-Ile, and omitting the coupling with Fmoc-Arg(Pmc) in Example 1.After workup the crude peptide can be purified by HPLC using a C-18column and a solvent system varying in gradient over 50 minutes from 5%to 100% acetonitrile/water containing 0.01% TFA. The pure fractions canbe lyophilized to provide N-Ac-D-aIle-Ser-Nva-Lys(Ac)-Arg-NHCH₂CH₃ asthe trifluoroacetate salt.

EXAMPLE 162 N-Ac-D-Ile-Thr-Ser-Ile-Arg-NHCH₂CH₃

The desired product can be prepared by substitutingFmoc-Arg(Pbf)-[4-(4-N-ethyl)methyl-3-methoxyphenoxy]butyryl AM resinethylamide resin for Fmoc-Pro Sieber ethylamide resin, Fmoc-Ser(O-tBu)for Fmoc-Nva, and omitting the coupling with Fmoc-Arg(Pmc) in Example 1.After workup the crude peptide can be purified by HPLC using a C-18column and a solvent system varying in gradient over 50 minutes from 5%to 100% acetonitrile/water containing 0.01% TFA. The pure fractions canbe lyophilized to provide N-Ac-D-Ile-Thr-Ser-Ile-Arg-NHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 163 N-Ac-D-Ile-Thr-NMeNva-Ile-Arg-NHCH₂CH₃

The desired product can be prepared by substitutingFmoc-Arg(Pbf)-[4-(4-N-ethyl)methyl-3-methoxyphenoxy]butyryl AM resinethylamide resin for Fmoc-Pro Sieber ethylamide resin, Fmoc-NMeNva forFmoc-Nva, omitting the coupling with Fmoc-Arg(Pmc), and using HATUinstead of HBTU in the coupling of the N-methyl-amino acid in Example 1.After workup the crude peptide can be purified by HPLC using a C-18column and a solvent system varying in gradient over 50 minutes from 5%to 100% acetonitrile/water containing 0.01% TFA. The pure fractions canbe lyophilized to provide N-Ac-D-Ile-Thr-NMeNva-Ile-Arg-NHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 164 N-Ac-Ser-Gln-Ile-Arg-NHCH₂CH₃ (SEQ ID NO:54)

The desired product can be prepared by substitutingFmoc-Arg(Pbf)-[4-(4-N-ethyl)methyl-3-methoxyphenoxy]butyryl AM resinethylamide resin for Fmoc-Pro Sieber ethylamide resin, Fmoc-Ser(O-tBu)for Fmoc-Thr(O-tBu), Fmoc-Gln(Trt) for Fmoc-Nva, and omitting thecoupling with Fmoc-Arg(Pmc) in Example 43. After workup the crudepeptide can be purified by HPLC using a C-18 column and a solvent systemvarying in gradient over 50 minutes from 5% to 100% acetonitrile/watercontaining 0.01% TFA. The pure fractions can be lyophilized to provideN-Ac-Ser-Gln-Ile-Arg-NHCH₂CH₃ as the trifluoroacetate salt.

EXAMPLE 165 N-Ac-Ser-Ser-Ile-Arg-NHCH₂CH₃ (SEQ ID NO:55)

The desired product can be prepared by substitutingFmoc-Arg(Pbf)-[4-(4-N-ethyl)methyl-3-methoxyphenoxy]butyryl AM resinethylamide resin for Fmoc-Pro Sieber ethylamide resin, Fmoc-Ser(O-tBu)for Fmoc-Thr(O-tBu) and Fmoc-Nva, and omitting the coupling withFmoc-Arg(Pmc) in Example 43 After workup the crude peptide can bepurified by HPLC using a C-18 column and a solvent system varying ingradient over 50 minutes from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions can be lyophilized to provideN-Ac-Ser-Ser-Ile-Arg-NHCH₂CH₃ as the trifluoroacetate salt.

EXAMPLE 166 N-Ac-Thr-Nva-Lys(Ac)-Arg-NH₂CH₃ (SEQ ID NO:56)

The desired product can be prepared by substitutingFmoc-Arg(Pbf)-[4-(4-N-ethyl)methyl-3-methoxyphenoxy]butyryl AM resinethylamide resin for Fmoc-Pro Sieber ethylamide resin, Fmoc-Lys(Ac) forFmoc-Ile, and omitting the coupling with Fmoc-Arg(Pmc) in Example 43.After workup the crude peptide can be purified by HPLC using a C-18column and a solvent system varying in gradient over 50 minutes from 5%to 100% acetonitrile/water containing 0.01% TFA. The pure fractions canbe lyophilized to provide N-Ac-Thr-Nva-Lys(Ac)-Arg-NHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 167 N-Ac-Thr-Gln-Lys(Ac)-Arg-NHCH₂CH₃ (SEQ ID NO:57)

The desired product can be prepared by substitutingFmoc-Arg(Pbf)-[4-(4-N-ethyl)methyl-3-methoxyphenoxy]butyryl AM resinethylamide resin for Fmoc-Pro Sieber ethylamide resin, Fmoc-Gln(Trt) forFmoc-Nva, Fmoc-Lys(Ac) for Fmoc-Ile, and omitting the coupling withFmoc-Arg(Pmc) in Example 43. After workup the crude peptide can bepurified by HPLC using a C-18 column and a solvent system varying ingradient over 50 minutes from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions can be lyophilized to provideN-Ac-Thr-Gln-Lys(Ac)-Arg-NHCH₂CH₃ as the trifluoroacetate salt

EXAMPLE 168 N-Ac-Thr-Ser-Ile-Arg-NHCH₂CH₃ (SEQ ID NO:58)

The desired product can be prepared by substitutingFmoc-Arg(Pbf)-[4-(4-N-ethyl)methyl-3-methoxyphenoxy]butyryl AM resinethylamide resin for Fmoc-Pro Sieber ethylamide resin, Fmoc-Ser(O-tBu)for Fmoc-Nva, and omitting the coupling with Fmoc-Arg(Pmc) in Example43. After workup the crude peptide can be purified by HPLC using a C-18column and a solvent system varying in gradient over 50 minutes from 5%to 100% acetonitrile/water containing 0.01% TFA. The pure fractions canbe lyophilized to provide N-Ac-Thr-Ser-Ile-Arg-NHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 169 N-Ac-Met-Nva-Ile-Arg-NHCH₂CH₃ (SEQ ID NO:59)

The desired product can be prepared by substitutingFmoc-Arg(Pbf)-[4-(4-N-ethyl)methyl-3-methoxyphenoxy]butyryl AM resinethylamide resin for Fmoc-Pro Sieber ethylamide resin, Fmoc-Met forFmoc-Thr(O-tBu), and omitting the coupling with Fmoc-Arg(Pmc) in Example43. After workup the crude peptide can be purified by HPLC using a C-18column and a solvent system varying in gradient over 50 minutes from 5%to 100% acetonitrile/water containing 0.01% TFA. The pure fractions canbe lyophilized to provide N-Ac-Met-Nva-Ile-Arg-NHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 170 N-Ac-Thr-NMeNva-Ile-Arg-NHCH₂CH₃ (SEQ ID NO:60)

The desired product can be prepared by substitutingFmoc-Arg(Pbf)-[4-(4-N-ethyl)methyl-3-methoxyphenoxy]butyryl AM resinethylamide resin for Fmoc-Pro Sieber ethylamide resin and Fmoc-NMeNvafor Fmoc-Nva, omitting the coupling with Fmoc-Arg(Pmc), and using HATUinstead of HBTU in the coupling of the N-methyl-amino acid in Example43. After workup the crude peptide can be purified by HPLC using a C-18column and a solvent system varying in gradient over 50 minutes from 5%to 100% acetonitrile/water containing 0.01% TFA. The pure fractions canbe lyophilized to provide N-Thr-NMeNva-Ile-Arg-NHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 171 N-Ac-D-Nva-Gln-Ile-Arg-NHCH₂CH₃

The desired product can be prepared by substitutingFmoc-Arg(Pbf)-[4-(4-N-ethyl)methyl-3-methoxyphenoxy]butyryl AM resinethylamide resin for Fmoc-Pro Sieber ethylamide resin, Fmoc-D-Nva forFmoc-Thr(O-tBu), Fmoc-Gln(Trt) for Fmoc-Nva, and omitting the couplingwith Fmoc-Arg(Pmc) in Example 43. After workup the crude peptide can bepurified by HPLC using a C-18 column and a solvent system varying ingradient over 50 minutes from 5% to 100% acetonitrile/water containing0.01% TFA. The pure fractions can be lyophilized to provideNAc-D-Nva-Gln-Ile-Arg-NHCH₂CH₃ as the trifluoroacetate salt.

EXAMPLE 172 N-Ac-Ser-Nva-Ile-Arg-NHCH₂CH₃ (SEQ ID NO:61)

The desired product can be prepared by substitutingFmoc-Arg(Pbf)-[4-(4-N-ethyl)methyl-3-methoxyphenoxy]butyryl AM resinethylamide resin for Fmoc-Pro Sieber ethylamide resin, Fmoc-Ser(O-tBu)for Fmoc-Thr(O-tBu), and omitting the coupling with Fmoc-Arg(Pmc) inExample 43. After workup the crude peptide can be purified by HPLC usinga C-18 column and a solvent system varying in gradient over 50 minutesfrom 5% to 100% acetonitrile/water containing 0.01% TFA. The purefractions can be lyophilized to provide N-Ac-Ser-Nva-Ile-Arg-NHCH₂CH₃ asthe trifluoroacetate salt.

EXAMPLE 173 N-Ac-D-Thr-Gln-Ile-Arg-NHCH₂CH₃

The desired product can be prepared by substitutingFmoc-Arg(Pbf)-[4-(4-N-ethyl)methyl-3-methoxyphenoxy]butyryl AM resinethylamide resin for Fmoc-Pro Sieber ethylamide resin, Fmoc-D-Thr(O-tBu)for Fmoc-Thr(O-tBu), Fmoc-Gln(Trt) for Fmoc-Nva, and omitting thecoupling with Fmoc-Arg(Pmc) in Example 43. After workup the crudepeptide can be purified by HPLC using a C-18 column and a solvent systemvarying in gradient over 50 minutes from 5% to 100% acetonitrile/watercontaining 0.01% TFA. The pure fractions can be lyophilized to provideN-Ac-D-Thr-Gln-Ile-Arg-NHCH₂CH₃ as the trifluoroacetate salt.

EXAMPLE 174 N-Ac-D-Ser-Gln-Ile-Arg-NHCH₂CH₃

The desired product can be prepared by substitutingFmoc-Arg(Pbf)-[4-(4-N-ethyl)methyl-3-methoxyphenoxy]butyryl AM resinethylamide resin for Fmoc-Pro Sieber ethylamide resin, Fmoc-DSer(O-tBu)for Fmoc-Thr(O-tBu), Fmoc-Gln(Trt) for Fmoc-Nva, and omitting thecoupling with Fmoc-Arg(Pmc) in Example 43. After workup the crudepeptide can be purified by HPLC using a C-18 column and a solvent systemvarying in gradient over 50 minutes from 5% to 100% acetonitrile/watercontaining 0.01% TFA. The pure fractions can be lyophilized to provideN-Ac-D-Ser-Gln-Ile-Arg-NHCH₂CH₃ as the trifluoroacetate salt.

It will be evident to one skilled in the art that the present inventionis not limited to the foregoing illustrative examples, and that it canbe embodied in other specific forms without departing from the essentialattributes thereof. It is therefore desired that the examples beconsidered in all respects as illustrative and not restrictive,reference being made to the appended claims, rather than to theforegoing examples, and all changes which come within the meaning andrange of equivalency of the claims are therefore intended to be embracedtherein.

1. A compound of formula (II) Xaa₁-Xaa₂-Xaa₃-Xaa₄-Xaa₅-Xaa₆-Xaa₇-Xaa₈  (II), (SEQ ID NO:2) or a therapeutically acceptable salt thereof, wherein Xaa₁ is selected from the group consisting of hydrogen and R—(CH₂)_(n)—C(O)—, wherein n is an integer from 0 to 8 and R is selected from the group consisting of alkoxy, alkyl, amino, aryl, carboxyl, cycloalkenyl, cycloalkyl, and heterocycle; Xaa₂ is selected from the group consisting of β-alanyl, D-alloisoleucyl D-4-chlorophenylalanyl, D-homophenylalanyl, D-isoleucyl,D-leucyl, D-penicillaminyl, and D-prolyl; Xaa₃ is selected from the group consisting of allothreonyl, aspartyl, glutaminyl, D-glutaminyl, N-methylglutaminyl, glycyl, histidyl, homoseryl, isoleucyl, lysyl(N-epsilon-acetyl), methionyl, seryl, N-methylseryl, threonyl, D-threonyl, tryptyl, tyrosyl, and tyrosyl(O-methyl); Xaa₄ is selected from the group consisting of N-methylalanyl, allothreonyl, glutaminyl, D-glutaminyl, glycyl, homoseryl, leucyl, lysyl(N-epsilon-acetyl), norleucyl, norvalyl, D-norvalyl, N-methylnorvalyl, ornithyl(N-delta-acetyl), 3-(3-pyridyl)alanyl, sarcosyl, seryl, N-methylseryl, threonyl, tryptyl, valyl and N-methylvalyl; Xaa₅ is selected from the group consisting of alanyl, alloisoleucyl, aspartyl, citrullyl, glutaminyl, isoleucyl, D-isoleucyl, N-methylisoleucyl, leucyl, D-leucyl, lysyl, lysyl(N-epsilon-acetyl), D-lysyl(N-epsilon-acetyl), norleucyl, norvalyl, phenylalanyl, prolyl, and D-prolyl; Xaa₆ is selected from the group consisting of arginyl, D-arginyl, citrullyl, histidyl, lysyl, lysyl(N-epsilon-isopropyl), ornithyl, and 3-(3-pyridyl)alanyl; Xaa₇ is absent or selected from the group consisting of N-methyl-D-alanyl, 2-aminobutyryl, 2-aminoisobutyryl, D-glutaminyl, homoprolyl, hydroxyprolyl, leucyl, phenylalanyl, prolyl, D-prolyl, and D-valyl; and Xaa₈ is selected from the group consisting of D-alanylamide, azaglycylamide, glycylamide, hydroxyl, D-lysyl(N-epsilon-acetyl)amide, a group represented by the formula —NH—(CH₂)_(n)—CHR¹R²; and a group represented by the formula —NHR³, wherein n is an integer from 0 to 8; R¹ is selected from the group consisting of hydrogen, alkyl, cycloalkenyl, and cycloalkyl; R² is selected from the group consisting of hydrogen, alkoxy, alkyl, aryl, cycloalkenyl, cycloalkyl, heterocycle, and hydroxyl, provided that when n is 0, R² is other than alkoxy or hydroxyl; and R³ is selected from the group consisting of hydrogen, cycloalkenyl, cycloalkyl, and hydroxyl.
 2. The compound of claim 1 selected from the group consisting of N-Ac-D-Pro-Thr-Nva-Ile-Arg-ProNHCH₂CH₃; N-Ac-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃; N-Ac-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₃; N-Ac-D-Hphe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃; N-Ac-D-4ClPhe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃; N-Ac-D-Pen-Thr-Nva-Ile-Arg-ProNHCH₂CH₃; N-Ac-bAla-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ (SEQ ID NO:49); N-Ac-bAla-Thr-Gln-Ile-Arg-ProNHCH₂CH₃ (SEQ ID NO:50); and N-Ac-D-Leu-Asp-Nva-Ile-Arg-ProNHCH₂CH₃.
 3. The compound of claim 1 wherein Xaa₂ is D-alloisoleucyl.
 4. The compound of claim 3 selected from the group consisting of N-Ac-D-aIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃; N-Ac-D-aIle-Ser-Ser-Ile-Arg-ProNHCH₂CH₃; N-Ac-D-aIle-Thr-Ser-Ile-Arg-ProNHCH₂CH₃; N-Ac-D-aIle-Tyr-Nva-Ile-Arg-ProNHCH₂CH₃; N-Ac-D-aIle-Ser-Thr-Ile-Arg-ProNHCH₂CH₃; N-Ac-D-aIle-Thr-Trp-Ile-Arg-ProNHCH₂CH₃; N-Ac-D-aIle-Ser-Ser-Lys(Ac)-Arg-ProNHCH₂CH₃; N-Ac-D-aIle-Ser-Ser-Nle-Arg-ProNHCH₂CH₃; N-Ac-D-aIle-Ser-Ser-Pro-Arg-ProNHCH₂CH₃; N-Ac-D-aIle-Ser-Ser-Nva-Arg-ProNHCH₂CH₃; N-Ac-D-aIle-Ser-Ser-Lys-Arg-ProNHCH₂CH₃; N-Ac-D-aIle-Ser-Ser-Ile-Arg-ProNHCH(CH₃)₂; N-Ac-D-aIle-Ser-Ser-Gln-Arg-ProNHCH₂CH₃; N-Ac-D-aIle-Ser-Ser-Cit-Arg-ProNHCH₂CH₃; N-Ac-D-aIle-Ser-Ser-Ile-Arg-NHCH₂CH₃; N-Ac-D-aIle-Thr-Nva-Ile-Arg-NHCH₂CH₃; and N-Ac-D-aIle-Ser-Nva-Lys(Ac)-Arg-NHCH₂CH₃.
 5. The compound of claim 1 wherein Xaa₂ is D-isoleucyl.
 6. The compound of claim 5 wherein Xaa₃ is selected from the group consisting of allothreonyl, aspartyl, glutaminyl, lysyl(N-epsilon-acetyl), methionyl, seryl, and tyrosyl.
 7. The compound of claim 6 selected from the group consisting of N-Ac-D-Ile-alloThr-Nva-Ile-Arg-ProNHCH₂CH₃; N-Ac-D-Ile-Ser-Gln-Ile-Arg-ProNHCH₂CH₃; N-Ac-D-Ile-Ser-Nva-Ile-Arg-Pro-D-AlaNH₂; N-Ac-D-Ile-Ser-Gln-D-Ile-Arg-ProNHCH₂CH₃; N-Ac-D-Ile-Gln-Nva-Ile-Arg-ProNHCH₂CH₃; N-Ac-D-Ile-Tyr-Nva-D-Ile-Arg-ProNHCH₂CH₃; N-Ac-D-Ile-Met-Nva-Ile-Arg-ProNHCH₂CH₃; N-Ac-D-Ile-Asp-Nva-Ile-Arg-ProNHCH₂CH₃; N-Ac-D-Ile-alloThr-Nva-Pro-Arg-ProNHCH₂CH₃; N-Ac-D-Ile-Met-Gln-Ile-Arg-ProNHCH₂CH₃; and N-Ac-D-Ile-Ser-Gln-Ile-Arg-NHCH₂CH₃.
 8. The compound of claim 5 wherein Xaa₃ is threonyl.
 9. The compound of claim 8 wherein Xaa₄ is selected from the group consisting of glutaminyl, D-glutaminyl, norleucyl, N-methylnorvalyl, seryl, and tryptyl.
 10. The compound of claim 9 selected from the group consisting of N-Ac-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃; N-Ac-D-Ile-Thr-Ser-Ile-Arg-Pro-D-AlaNH₂; N-Ac-D-Ile-Thr-Trp-D-Ile-Arg-ProNHCH₂CH₃; N-Ac-D-Ile-Thr-Trp-Ile-Arg-Pro-D-AlaNH₂; N-Ac-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂; N-Ac-D-Ile-Thr-Nle-Ile-Arg-ProNHCH₂CH₃; N-Ac-D-Ile-Thr-D-Gln-Ile-Arg-ProNHCH₂CH₃; N-Ac-D-Ile-Thr-Gln-Ile-Arg-NHCH₂CH₃; N-Ac-D-Ile-Thr-Gln-Lys(Ac)-Arg-NHCH₂CH₃; N-Ac-D-Ile-Thr-Ser-Ile-Arg-NHCH₂CH₃; and N-Ac-D-Ile-Thr-NMeNva-Ile-Arg-NHCH₂CH₃.
 11. The compound of claim 8 wherein Xaa₄ is norvalyl.
 12. The compound of claim 11 selected from the group consisting of N-Ac-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃; N-Ac-D-Ile-Thr-Nva-Pro-Arg-ProNHCH₂CH₃; N-Ac-D-Ile-Thr-Nva-Ile-Arg-D-ProNHCH₂CH₃; N-Ac-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH₂; N-Ac-D-Ile-Thr-Nva-D-Leu-Arg-ProNHCH₂CH₃; N-Ac-D-Ile-Thr-Nva-D-Ile-Arg-ProNHCH₂CH₃; N-Ac-D-Ile-Thr-Nva-Ile-Arg-Pro-D-Lys(Ac)NH₂; N-Ac-D-Ile-Thr-Nva-D-Lys(Ac)-Arg-ProNHCH₂CH₃; N-Ac-D-Ile-Thr-Nva-Lys(Ac)-Arg-ProNHCH₂CH₃; N-Ac-D-Ile-Thr-Nva-Ile-His-ProNHCH₂CH₃; N-Ac-D-Ile-Thr-Nva-Ile-3-Pal-ProNHCH₂CH₃; N-Ac-D-Ile-Thr-Nva-Ile-D-Arg-ProNHCH₂CH₃; N-Ac-D-Ile-Thr-Nva-Ile-ArgNHCH₂CH₃; and N-Ac-D-Ile-Thr-Nva-Lys(Ac)-Arg-NHCH₂CH₃. 